CIDeRplusGeneral Information:
| Id: | 6,363 |
| Diseases: |
Diabetes mellitus, type II
- [OMIM]
Insulin resistance Pancreatic cancer - [OMIM] |
| Mammalia | |
| review | |
| Reference: | Cohen R et al.(2015) Targeting cancer cell metabolism in pancreatic adenocarcinoma Oncotarget 19 [PMID: 26164081] |
Interaction Information:
| Comment | Pancreatic ductal adenocarcinomas (PDAC) are characterized by a prominent desmoplastic stromal reaction, and the extent of the stroma is often greater than the epithelial component of the tumor (up to 80% of tumor volume). Activated pancreatic stellate cells (PSC) are responsible for the excessive production of extracellular matrix. The resulting dense and fibrotic stroma compresses vessels and generates high interstitial pressure thereby limiting tumor vascularization. As a consequence, tumor cells are confronted with hypoxia and nutrient deprivation. |
|
Formal Description Interaction-ID: 59619 |
|
| Comment | Pancreatic ductal adenocarcinomas (PDAC) are characterized by a prominent desmoplastic stromal reaction, and the extent of the stroma is often greater than the epithelial component of the tumor (up to 80% of tumor volume). Activated pancreatic stellate cells (PSC) are responsible for the excessive production of extracellular matrix. The resulting dense and fibrotic stroma compresses vessels and generates high interstitial pressure thereby limiting tumor vascularization. As a consequence, tumor cells are confronted with hypoxia and nutrient deprivation. |
|
Formal Description Interaction-ID: 59812 |
|
| Comment | Pancreatic ductal adenocarcinomas (PDAC) are characterized by a prominent desmoplastic stromal reaction, and the extent of the stroma is often greater than the epithelial component of the tumor (up to 80% of tumor volume). Activated pancreatic stellate cells (PSC) are responsible for the excessive production of extracellular matrix. The resulting dense and fibrotic stroma compresses vessels and generates high interstitial pressure thereby limiting tumor vascularization. As a consequence, tumor cells are confronted with hypoxia and nutrient deprivation. |
|
Formal Description Interaction-ID: 59813 |
cellular component affects_activity of phenotype decreased tumor vascularization |
| Comment | Preclinical studies in pancreatic ductal adenocarcinoma (PDAC) models showed that hypoxia increases cancer cell proliferation, survival, epithelial-to-mesenchymal transition (EMT), invasiveness, and metastasis, as well as resistance to chemotherapy and radiotherapy, through hypoxia-inducible factor (HIF)-1alpha-dependent and -independent mechanisms. |
|
Formal Description Interaction-ID: 59814 |
|
| Comment | Preclinical studies in pancreatic ductal adenocarcinoma (PDAC) models showed that hypoxia increases cancer cell proliferation, survival, epithelial-to-mesenchymal transition (EMT), invasiveness, and metastasis, as well as resistance to chemotherapy and radiotherapy, through hypoxia-inducible factor (HIF)-1alpha-dependent and -independent mechanisms. |
|
Formal Description Interaction-ID: 59819 |
|
| Comment | Preclinical studies in pancreatic ductal adenocarcinoma (PDAC) models showed that hypoxia increases cancer cell proliferation, survival, epithelial-to-mesenchymal transition (EMT), invasiveness, and metastasis, as well as resistance to chemotherapy and radiotherapy, through hypoxia-inducible factor (HIF)-1alpha-dependent and -independent mechanisms. |
|
Formal Description Interaction-ID: 59820 |
|
| Comment | Preclinical studies in pancreatic ductal adenocarcinoma (PDAC) models showed that hypoxia increases cancer cell proliferation, survival, epithelial-to-mesenchymal transition (EMT), invasiveness, and metastasis, as well as resistance to chemotherapy and radiotherapy, through hypoxia-inducible factor (HIF)-1alpha-dependent and -independent mechanisms. |
|
Formal Description Interaction-ID: 59821 |
|
| Comment | In the presence of oxygen, normal cells produce ATP from glucose-derived pyruvate by oxidative phosphorylation (OXPHOS) via the mitochondrial tricarboxylic acid (TCA) cycle. In the 1920s, Otto Warburg observed that some proliferative tissues, notably tumor cells, display increased glucose uptake and preferentially metabolize glucose-derived pyruvate to lactate even in the presence of oxygen. This phenomenon of aerobic glycolysis is also known as the ‚ÄúWarburg effect‚ÄĚ. |
|
Formal Description Interaction-ID: 59823 |
disease Cancer increases_activity of process aerobic glycolysis |
| Comment | The glycolytic switch is an early phenomenon characterized by increased expression of lactate dehydrogenase (LDH, that converts pyruvate into lactate) and inactivation of pyruvate dehydrogenase (PDH, that converts pyruvate into acetyl-CoA for the TCA cycle). The glycolytic switch is thought to be driven by the hypoxic tumor microenvironment through HIF-1alpha activation, aberrant signaling due to oncogene activation (e.g., Ras, PI3K/mTOR, c-Myc), tumor suppressor gene inactivation (e.g., p53), or by mutations in the OXPHOS pathway. |
|
Formal Description Interaction-ID: 59824 |
|
| Comment | The glycolytic switch is an early phenomenon characterized by increased expression of lactate dehydrogenase (LDH, that converts pyruvate into lactate) and inactivation of pyruvate dehydrogenase (PDH, that converts pyruvate into acetyl-CoA for the TCA cycle). The glycolytic switch is thought to be driven by the hypoxic tumor microenvironment through HIF-1alpha activation, aberrant signaling due to oncogene activation (e.g., Ras, PI3K/mTOR, c-Myc), tumor suppressor gene inactivation (e.g., p53), or by mutations in the OXPHOS pathway. |
|
Formal Description Interaction-ID: 59825 |
process glycolytic switch increases_activity of process aerobic glycolysis |
| Comment | The glycolytic switch is an early phenomenon characterized by increased expression of lactate dehydrogenase (LDH, that converts pyruvate into lactate) and inactivation of pyruvate dehydrogenase (PDH, that converts pyruvate into acetyl-CoA for the TCA cycle). The glycolytic switch is thought to be driven by the hypoxic tumor microenvironment through HIF-1alpha activation, aberrant signaling due to oncogene activation (e.g., Ras, PI3K/mTOR, c-Myc), tumor suppressor gene inactivation (e.g., p53), or by mutations in the OXPHOS pathway. |
|
Formal Description Interaction-ID: 59826 |
process glycolytic switch increases_activity of complex/PPI Lactate dehydrogenase |
| Comment | The glycolytic switch is an early phenomenon characterized by increased expression of lactate dehydrogenase (LDH, that converts pyruvate into lactate) and inactivation of pyruvate dehydrogenase (PDH, that converts pyruvate into acetyl-CoA for the TCA cycle). The glycolytic switch is thought to be driven by the hypoxic tumor microenvironment through HIF-1alpha activation, aberrant signaling due to oncogene activation (e.g., Ras, PI3K/mTOR, c-Myc), tumor suppressor gene inactivation (e.g., p53), or by mutations in the OXPHOS pathway. |
|
Formal Description Interaction-ID: 59827 |
process glycolytic switch decreases_activity of complex/PPI Pyruvate dehydrogenase complex |
| Comment | The glycolytic switch is an early phenomenon characterized by increased expression of lactate dehydrogenase (LDH, that converts pyruvate into lactate) and inactivation of pyruvate dehydrogenase (PDH, that converts pyruvate into acetyl-CoA for the TCA cycle). The glycolytic switch is thought to be driven by the hypoxic tumor microenvironment through HIF-1alpha activation, aberrant signaling due to oncogene activation (e.g., Ras, PI3K/mTOR, c-Myc), tumor suppressor gene inactivation (e.g., p53), or by mutations in the OXPHOS pathway. |
|
Formal Description Interaction-ID: 59828 |
|
| Comment | The glycolytic switch is an early phenomenon characterized by increased expression of lactate dehydrogenase (LDH, that converts pyruvate into lactate) and inactivation of pyruvate dehydrogenase (PDH, that converts pyruvate into acetyl-CoA for the TCA cycle). The glycolytic switch is thought to be driven by the hypoxic tumor microenvironment through HIF-1alpha activation, aberrant signaling due to oncogene activation (e.g., Ras, PI3K/mTOR, c-Myc), tumor suppressor gene inactivation (e.g., p53), or by mutations in the OXPHOS pathway. |
|
Formal Description Interaction-ID: 59829 |
|
| Drugbank entries | Show/Hide entries for HIF1A |
| Comment | The glycolytic switch is an early phenomenon characterized by increased expression of lactate dehydrogenase (LDH, that converts pyruvate into lactate) and inactivation of pyruvate dehydrogenase (PDH, that converts pyruvate into acetyl-CoA for the TCA cycle). The glycolytic switch is thought to be driven by the hypoxic tumor microenvironment through HIF-1alpha activation, aberrant signaling due to oncogene activation (e.g., Ras, PI3K/mTOR, c-Myc), tumor suppressor gene inactivation (e.g., p53), or by mutations in the OXPHOS pathway. |
|
Formal Description Interaction-ID: 59830 |
|
| Comment | The glycolytic switch is an early phenomenon characterized by increased expression of lactate dehydrogenase (LDH, that converts pyruvate into lactate) and inactivation of pyruvate dehydrogenase (PDH, that converts pyruvate into acetyl-CoA for the TCA cycle). The glycolytic switch is thought to be driven by the hypoxic tumor microenvironment through HIF-1alpha activation, aberrant signaling due to oncogene activation (e.g., Ras, PI3K/mTOR, c-Myc), tumor suppressor gene inactivation (e.g., p53), or by mutations in the OXPHOS pathway. |
|
Formal Description Interaction-ID: 59831 |
|
| Comment | The glycolytic switch is an early phenomenon characterized by increased expression of lactate dehydrogenase (LDH, that converts pyruvate into lactate) and inactivation of pyruvate dehydrogenase (PDH, that converts pyruvate into acetyl-CoA for the TCA cycle). The glycolytic switch is thought to be driven by the hypoxic tumor microenvironment through HIF-1alpha activation, aberrant signaling due to oncogene activation (e.g., Ras, PI3K/mTOR, c-Myc), tumor suppressor gene inactivation (e.g., p53), or by mutations in the OXPHOS pathway. |
|
Formal Description Interaction-ID: 59832 |
|
| Comment | The glycolytic switch is an early phenomenon characterized by increased expression of lactate dehydrogenase (LDH, that converts pyruvate into lactate) and inactivation of pyruvate dehydrogenase (PDH, that converts pyruvate into acetyl-CoA for the TCA cycle). The glycolytic switch is thought to be driven by the hypoxic tumor microenvironment through HIF-1alpha activation, aberrant signaling due to oncogene activation (e.g., Ras, PI3K/mTOR, c-Myc), tumor suppressor gene inactivation (e.g., p53), or by mutations in the OXPHOS pathway. |
|
Formal Description Interaction-ID: 59833 |
|
| Drugbank entries | Show/Hide entries for TP53 |
| Comment | Constitutively activated K-Ras, present in more than 90% of pancreatic ductal adenocarcinoma (PDAC), has a key role in metabolic reprogramming and particularly in the glycolytic switch. |
|
Formal Description Interaction-ID: 59834 |
|
| Drugbank entries | Show/Hide entries for KRAS |
| Comment | Constitutively activated K-Ras, present in more than 90% of pancreatic ductal adenocarcinoma (PDAC), has a key role in metabolic reprogramming and particularly in the glycolytic switch. |
|
Formal Description Interaction-ID: 59835 |
|
| Drugbank entries | Show/Hide entries for KRAS |
| Comment | Oncogenic KRAS upregulates expression of glucose transporter (GLUT)-1 (increasing glucose influx) and of the hexokinase (HK) 1‚Äď2 and phosphofructokinase enzymes, which speed up glycolytic activity. Oncogenic KRAS also supports biomass synthesis (i.e. proteins, nucleic acids etc.) required for cancer cell proliferation by rewiring glucose toward anabolic pathways, such as the pentose phosphate pathway (PPP), while maintaining a low level of reactive oxygen species (ROS) by limiting ROS production and ROS-related apoptosis. |
|
Formal Description Interaction-ID: 59836 |
|
| Drugbank entries | Show/Hide entries for KRAS |
| Comment | Oncogenic KRAS upregulates expression of glucose transporter (GLUT)-1 (increasing glucose influx) and of the hexokinase (HK) 1‚Äď2 and phosphofructokinase enzymes, which speed up glycolytic activity. Oncogenic KRAS also supports biomass synthesis (i.e. proteins, nucleic acids etc.) required for cancer cell proliferation by rewiring glucose toward anabolic pathways, such as the pentose phosphate pathway (PPP), while maintaining a low level of reactive oxygen species (ROS) by limiting ROS production and ROS-related apoptosis. |
|
Formal Description Interaction-ID: 59837 |
|
| Drugbank entries | Show/Hide entries for KRAS or HK1 |
| Comment | Oncogenic KRAS upregulates expression of glucose transporter (GLUT)-1 (increasing glucose influx) and of the hexokinase (HK) 1‚Äď2 and phosphofructokinase enzymes, which speed up glycolytic activity. Oncogenic KRAS also supports biomass synthesis (i.e. proteins, nucleic acids etc.) required for cancer cell proliferation by rewiring glucose toward anabolic pathways, such as the pentose phosphate pathway (PPP), while maintaining a low level of reactive oxygen species (ROS) by limiting ROS production and ROS-related apoptosis. |
|
Formal Description Interaction-ID: 59838 |
|
| Drugbank entries | Show/Hide entries for KRAS |
| Comment | Oncogenic KRAS upregulates expression of glucose transporter (GLUT)-1 (increasing glucose influx) and of the hexokinase (HK) 1‚Äď2 and phosphofructokinase enzymes, which speed up glycolytic activity. Oncogenic KRAS also supports biomass synthesis (i.e. proteins, nucleic acids etc.) required for cancer cell proliferation by rewiring glucose toward anabolic pathways, such as the pentose phosphate pathway (PPP), while maintaining a low level of reactive oxygen species (ROS) by limiting ROS production and ROS-related apoptosis. |
|
Formal Description Interaction-ID: 59839 |
|
| Drugbank entries | Show/Hide entries for KRAS |
| Comment | Oncogenic KRAS upregulates expression of glucose transporter (GLUT)-1 (increasing glucose influx) and of the hexokinase (HK) 1‚Äď2 and phosphofructokinase enzymes, which speed up glycolytic activity. Oncogenic KRAS also supports biomass synthesis (i.e. proteins, nucleic acids etc.) required for cancer cell proliferation by rewiring glucose toward anabolic pathways, such as the pentose phosphate pathway (PPP), while maintaining a low level of reactive oxygen species (ROS) by limiting ROS production and ROS-related apoptosis. |
|
Formal Description Interaction-ID: 59840 |
|
| Drugbank entries | Show/Hide entries for KRAS |
| Comment | Oncogenic KRAS upregulates expression of glucose transporter (GLUT)-1 (increasing glucose influx) and of the hexokinase (HK) 1‚Äď2 and phosphofructokinase enzymes, which speed up glycolytic activity. Oncogenic KRAS also supports biomass synthesis (i.e. proteins, nucleic acids etc.) required for cancer cell proliferation by rewiring glucose toward anabolic pathways, such as the pentose phosphate pathway (PPP), while maintaining a low level of reactive oxygen species (ROS) by limiting ROS production and ROS-related apoptosis. |
|
Formal Description Interaction-ID: 59841 |
|
| Drugbank entries | Show/Hide entries for KRAS |
| Comment | Oncogenic KRAS upregulates expression of glucose transporter (GLUT)-1 (increasing glucose influx) and of the hexokinase (HK) 1‚Äď2 and phosphofructokinase enzymes, which speed up glycolytic activity. Oncogenic KRAS also supports biomass synthesis (i.e. proteins, nucleic acids etc.) required for cancer cell proliferation by rewiring glucose toward anabolic pathways, such as the pentose phosphate pathway (PPP), while maintaining a low level of reactive oxygen species (ROS) by limiting ROS production and ROS-related apoptosis. |
|
Formal Description Interaction-ID: 59842 |
|
| Drugbank entries | Show/Hide entries for KRAS |
| Comment | TP53 loss-of-function (50% of PDAC) also contributes to the glycolytic switch through deregulation of GLUT1 and GLUT4 transcription and loss of expression of TIGAR (TP53-inductible glycolytic and apoptotic regulator) which acts as a fructose-2, 6-biphosphatase (FBP-ase). Although the physiological substrate of TIGAR remains controversial, when silenced, FBP levels increase enhancing pyruvate kinase (PKM) glycolytic activity. Interestingly, genetic mutations may be a consequence of metabolic stress, such as glucose deprivation, dynamically interconnecting oncogenic and metabolic alterations. |
|
Formal Description Interaction-ID: 59843 |
|
| Drugbank entries | Show/Hide entries for TP53 |
| Comment | TP53 loss-of-function (50% of PDAC) also contributes to the glycolytic switch through deregulation of GLUT1 and GLUT4 transcription and loss of expression of TIGAR (TP53-inductible glycolytic and apoptotic regulator) which acts as a fructose-2, 6-biphosphatase (FBP-ase). Although the physiological substrate of TIGAR remains controversial, when silenced, FBP levels increase enhancing pyruvate kinase (PKM) glycolytic activity. Interestingly, genetic mutations may be a consequence of metabolic stress, such as glucose deprivation, dynamically interconnecting oncogenic and metabolic alterations. |
|
Formal Description Interaction-ID: 59844 |
|
| Drugbank entries | Show/Hide entries for TP53 |
| Comment | TP53 loss-of-function (50% of PDAC) also contributes to the glycolytic switch through deregulation of GLUT1 and GLUT4 transcription and loss of expression of TIGAR (TP53-inductible glycolytic and apoptotic regulator) which acts as a fructose-2, 6-biphosphatase (FBP-ase). Although the physiological substrate of TIGAR remains controversial, when silenced, FBP levels increase enhancing pyruvate kinase (PKM) glycolytic activity. Interestingly, genetic mutations may be a consequence of metabolic stress, such as glucose deprivation, dynamically interconnecting oncogenic and metabolic alterations. |
|
Formal Description Interaction-ID: 59845 |
|
| Drugbank entries | Show/Hide entries for TP53 |
| Comment | TP53 loss-of-function (50% of PDAC) also contributes to the glycolytic switch through deregulation of GLUT1 and GLUT4 transcription and loss of expression of TIGAR (TP53-inductible glycolytic and apoptotic regulator) which acts as a fructose-2, 6-biphosphatase (FBP-ase). Although the physiological substrate of TIGAR remains controversial, when silenced, FBP levels increase enhancing pyruvate kinase (PKM) glycolytic activity. Interestingly, genetic mutations may be a consequence of metabolic stress, such as glucose deprivation, dynamically interconnecting oncogenic and metabolic alterations. |
|
Formal Description Interaction-ID: 59846 |
|
| Drugbank entries | Show/Hide entries for TP53 |
| Comment | The glycolytic switch also mediates interconnections between tumor compartments. Far from being a waste product of the Warburg effect, lactate may be an important vector for tumor-stroma interactions and symbiotic spatial energy fuel exchange between cell compartments within the tumor. Lactate produced by hypoxic cancer cells can diffuse to the extracellular environment through lactate transporter MCT-4 and be taken up by normoxic cancer cells through MCT-1 to be used for oxidative metabolism, thereby sparing glucose for hypoxic cancer cells. Lactate also ‚Äúfeeds‚ÄĚ stromal cells providing a fuel source for OXPHOS. |
|
Formal Description Interaction-ID: 59847 |
|
| Comment | The glycolytic switch also mediates interconnections between tumor compartments. Far from being a waste product of the Warburg effect, lactate may be an important vector for tumor-stroma interactions and symbiotic spatial energy fuel exchange between cell compartments within the tumor. Lactate produced by hypoxic cancer cells can diffuse to the extracellular environment through lactate transporter MCT-4 and be taken up by normoxic cancer cells through MCT-1 to be used for oxidative metabolism, thereby sparing glucose for hypoxic cancer cells. Lactate also ‚Äúfeeds‚ÄĚ stromal cells providing a fuel source for OXPHOS. |
|
Formal Description Interaction-ID: 59848 |
|
| Drugbank entries | Show/Hide entries for SLC16A4 |
| Comment | The glycolytic switch also mediates interconnections between tumor compartments. Far from being a waste product of the Warburg effect, lactate may be an important vector for tumor-stroma interactions and symbiotic spatial energy fuel exchange between cell compartments within the tumor. Lactate produced by hypoxic cancer cells can diffuse to the extracellular environment through lactate transporter MCT-4 and be taken up by normoxic cancer cells through MCT-1 to be used for oxidative metabolism, thereby sparing glucose for hypoxic cancer cells. Lactate also ‚Äúfeeds‚ÄĚ stromal cells providing a fuel source for OXPHOS. |
|
Formal Description Interaction-ID: 59849 |
|
| Drugbank entries | Show/Hide entries for SLC16A1 |
| Comment | The glycolytic switch also mediates interconnections between tumor compartments. Far from being a waste product of the Warburg effect, lactate may be an important vector for tumor-stroma interactions and symbiotic spatial energy fuel exchange between cell compartments within the tumor. Lactate produced by hypoxic cancer cells can diffuse to the extracellular environment through lactate transporter MCT-4 and be taken up by normoxic cancer cells through MCT-1 to be used for oxidative metabolism, thereby sparing glucose for hypoxic cancer cells. Lactate also ‚Äúfeeds‚ÄĚ stromal cells providing a fuel source for OXPHOS. |
|
Formal Description Interaction-ID: 59850 |
|
| Comment | Acidification of the microenvironment by lactic acid contributes to pro-tumor immunologic remodeling by promoting chronic inflammation, while suppressing T-cell mediated adaptive immune response. Lactate-dependent interleukin-17 and interleukin-23 production can induce an inflammatory tumor environment that will result in the attraction of pro-tumoral immune cells. |
|
Formal Description Interaction-ID: 59851 |
|
| Comment | Acidification of the microenvironment by lactic acid contributes to pro-tumor immunologic remodeling by promoting chronic inflammation, while suppressing T-cell mediated adaptive immune response. Lactate-dependent interleukin-17 and interleukin-23 production can induce an inflammatory tumor environment that will result in the attraction of pro-tumoral immune cells. |
|
Formal Description Interaction-ID: 59852 |
|
| Comment | Acidification of the microenvironment by lactic acid contributes to pro-tumor immunologic remodeling by promoting chronic inflammation, while suppressing T-cell mediated adaptive immune response. Lactate-dependent interleukin-17 and interleukin-23 production can induce an inflammatory tumor environment that will result in the attraction of pro-tumoral immune cells. |
|
Formal Description Interaction-ID: 59853 |
|
| Comment | Elevated plasma levels of all three proteinogenic, essential, BCAA (isoleucine, leucine and valine) are associated with future diagnosis of PDAC. |
|
Formal Description Interaction-ID: 59854 |
phenotype increased circulating isoleucine level affects_activity of disease |
| Comment | Elevated plasma levels of all three proteinogenic, essential, BCAA (isoleucine, leucine and valine) are associated with future diagnosis of PDAC. |
|
Formal Description Interaction-ID: 59855 |
phenotype increased circulating leucine level affects_activity of disease |
| Comment | Elevated plasma levels of all three proteinogenic, essential, BCAA (isoleucine, leucine and valine) are associated with future diagnosis of PDAC. |
|
Formal Description Interaction-ID: 59856 |
phenotype increased circulating valine level affects_activity of disease |
| Comment | Although glutamine is a non-essential AA, most cancer cells exhibit glutamine addiction. The metabolic fate of glutamine is multifaceted; it can be used for lipid biosynthesis, as a nitrogen donor for AA and nucleotide biosynthesis, as a carbonic substrate for the re-feeding of the mitochondrial TCA cycle through a phenomenon called anaplerosis, and even as fuel for cell energy production. PDAC cells metabolize glutamine through a non-canonical pathway in which transaminases play a crucial role. Whereas most cells use glutamate dehydrogenase (GDH-1) to convert glutamine-derived glutamate into alpha-ketoglutarate in the mitochondria to fuel the TCA cycle, PDAC relies on a distinct pathway in which glutamine-derived aspartate is transported into the cytoplasm where it can be converted into oxaloacetate by aspartate transaminase (i.e. glutamic-oxaloacetic transaminase [GOT-1]), then into malate, and finally into pyruvate. |
|
Formal Description Interaction-ID: 59857 |
disease Cancer increases_activity of phenotype glutamine addiction |
| Comment | Although glutamine is a non-essential AA, most cancer cells exhibit glutamine addiction. The metabolic fate of glutamine is multifaceted; it can be used for lipid biosynthesis, as a nitrogen donor for AA and nucleotide biosynthesis, as a carbonic substrate for the re-feeding of the mitochondrial TCA cycle through a phenomenon called anaplerosis, and even as fuel for cell energy production. PDAC cells metabolize glutamine through a non-canonical pathway in which transaminases play a crucial role. Whereas most cells use glutamate dehydrogenase (GDH-1) to convert glutamine-derived glutamate into alpha-ketoglutarate in the mitochondria to fuel the TCA cycle, PDAC relies on a distinct pathway in which glutamine-derived aspartate is transported into the cytoplasm where it can be converted into oxaloacetate by aspartate transaminase (i.e. glutamic-oxaloacetic transaminase [GOT-1]), then into malate, and finally into pyruvate. |
|
Formal Description Interaction-ID: 59858 |
|
| Comment | Although glutamine is a non-essential AA, most cancer cells exhibit glutamine addiction. The metabolic fate of glutamine is multifaceted; it can be used for lipid biosynthesis, as a nitrogen donor for AA and nucleotide biosynthesis, as a carbonic substrate for the re-feeding of the mitochondrial TCA cycle through a phenomenon called anaplerosis, and even as fuel for cell energy production. PDAC cells metabolize glutamine through a non-canonical pathway in which transaminases play a crucial role. Whereas most cells use glutamate dehydrogenase (GDH-1) to convert glutamine-derived glutamate into alpha-ketoglutarate in the mitochondria to fuel the TCA cycle, PDAC relies on a distinct pathway in which glutamine-derived aspartate is transported into the cytoplasm where it can be converted into oxaloacetate by aspartate transaminase (i.e. glutamic-oxaloacetic transaminase [GOT-1]), then into malate, and finally into pyruvate. |
|
Formal Description Interaction-ID: 59859 |
drug/chemical compound increases_activity of |
| Comment | Although glutamine is a non-essential AA, most cancer cells exhibit glutamine addiction. The metabolic fate of glutamine is multifaceted; it can be used for lipid biosynthesis, as a nitrogen donor for AA and nucleotide biosynthesis, as a carbonic substrate for the re-feeding of the mitochondrial TCA cycle through a phenomenon called anaplerosis, and even as fuel for cell energy production. PDAC cells metabolize glutamine through a non-canonical pathway in which transaminases play a crucial role. Whereas most cells use glutamate dehydrogenase (GDH-1) to convert glutamine-derived glutamate into alpha-ketoglutarate in the mitochondria to fuel the TCA cycle, PDAC relies on a distinct pathway in which glutamine-derived aspartate is transported into the cytoplasm where it can be converted into oxaloacetate by aspartate transaminase (i.e. glutamic-oxaloacetic transaminase [GOT-1]), then into malate, and finally into pyruvate. |
|
Formal Description Interaction-ID: 59860 |
|
| Comment | Although glutamine is a non-essential AA, most cancer cells exhibit glutamine addiction. The metabolic fate of glutamine is multifaceted; it can be used for lipid biosynthesis, as a nitrogen donor for AA and nucleotide biosynthesis, as a carbonic substrate for the re-feeding of the mitochondrial TCA cycle through a phenomenon called anaplerosis, and even as fuel for cell energy production. PDAC cells metabolize glutamine through a non-canonical pathway in which transaminases play a crucial role. Whereas most cells use glutamate dehydrogenase (GDH-1) to convert glutamine-derived glutamate into alpha-ketoglutarate in the mitochondria to fuel the TCA cycle, PDAC relies on a distinct pathway in which glutamine-derived aspartate is transported into the cytoplasm where it can be converted into oxaloacetate by aspartate transaminase (i.e. glutamic-oxaloacetic transaminase [GOT-1]), then into malate, and finally into pyruvate. |
|
Formal Description Interaction-ID: 59861 |
|
| Comment | Although glutamine is a non-essential AA, most cancer cells exhibit glutamine addiction. The metabolic fate of glutamine is multifaceted; it can be used for lipid biosynthesis, as a nitrogen donor for AA and nucleotide biosynthesis, as a carbonic substrate for the re-feeding of the mitochondrial TCA cycle through a phenomenon called anaplerosis, and even as fuel for cell energy production. PDAC cells metabolize glutamine through a non-canonical pathway in which transaminases play a crucial role. Whereas most cells use glutamate dehydrogenase (GDH-1) to convert glutamine-derived glutamate into alpha-ketoglutarate in the mitochondria to fuel the TCA cycle, PDAC relies on a distinct pathway in which glutamine-derived aspartate is transported into the cytoplasm where it can be converted into oxaloacetate by aspartate transaminase (i.e. glutamic-oxaloacetic transaminase [GOT-1]), then into malate, and finally into pyruvate. |
|
Formal Description Interaction-ID: 59862 |
|
| Comment | Although glutamine is a non-essential AA, most cancer cells exhibit glutamine addiction. The metabolic fate of glutamine is multifaceted; it can be used for lipid biosynthesis, as a nitrogen donor for AA and nucleotide biosynthesis, as a carbonic substrate for the re-feeding of the mitochondrial TCA cycle through a phenomenon called anaplerosis, and even as fuel for cell energy production. PDAC cells metabolize glutamine through a non-canonical pathway in which transaminases play a crucial role. Whereas most cells use glutamate dehydrogenase (GDH-1) to convert glutamine-derived glutamate into alpha-ketoglutarate in the mitochondria to fuel the TCA cycle, PDAC relies on a distinct pathway in which glutamine-derived aspartate is transported into the cytoplasm where it can be converted into oxaloacetate by aspartate transaminase (i.e. glutamic-oxaloacetic transaminase [GOT-1]), then into malate, and finally into pyruvate. |
|
Formal Description Interaction-ID: 59863 |
|
| Drugbank entries | Show/Hide entries for GOT1 |
| Comment | Although glutamine is a non-essential AA, most cancer cells exhibit glutamine addiction. The metabolic fate of glutamine is multifaceted; it can be used for lipid biosynthesis, as a nitrogen donor for AA and nucleotide biosynthesis, as a carbonic substrate for the re-feeding of the mitochondrial TCA cycle through a phenomenon called anaplerosis, and even as fuel for cell energy production. PDAC cells metabolize glutamine through a non-canonical pathway in which transaminases play a crucial role. Whereas most cells use glutamate dehydrogenase (GDH-1) to convert glutamine-derived glutamate into alpha-ketoglutarate in the mitochondria to fuel the TCA cycle, PDAC relies on a distinct pathway in which glutamine-derived aspartate is transported into the cytoplasm where it can be converted into oxaloacetate by aspartate transaminase (i.e. glutamic-oxaloacetic transaminase [GOT-1]), then into malate, and finally into pyruvate. |
|
Formal Description Interaction-ID: 59864 |
gene/protein increases_quantity of drug/chemical compound |
| Drugbank entries | Show/Hide entries for GOT1 |
| Comment | Although glutamine is a non-essential AA, most cancer cells exhibit glutamine addiction. The metabolic fate of glutamine is multifaceted; it can be used for lipid biosynthesis, as a nitrogen donor for AA and nucleotide biosynthesis, as a carbonic substrate for the re-feeding of the mitochondrial TCA cycle through a phenomenon called anaplerosis, and even as fuel for cell energy production. PDAC cells metabolize glutamine through a non-canonical pathway in which transaminases play a crucial role. Whereas most cells use glutamate dehydrogenase (GDH-1) to convert glutamine-derived glutamate into alpha-ketoglutarate in the mitochondria to fuel the TCA cycle, PDAC relies on a distinct pathway in which glutamine-derived aspartate is transported into the cytoplasm where it can be converted into oxaloacetate by aspartate transaminase (i.e. glutamic-oxaloacetic transaminase [GOT-1]), then into malate, and finally into pyruvate. |
|
Formal Description Interaction-ID: 59865 |
drug/chemical compound affects_quantity of drug/chemical compound |
| Comment | Although glutamine is a non-essential AA, most cancer cells exhibit glutamine addiction. The metabolic fate of glutamine is multifaceted; it can be used for lipid biosynthesis, as a nitrogen donor for AA and nucleotide biosynthesis, as a carbonic substrate for the re-feeding of the mitochondrial TCA cycle through a phenomenon called anaplerosis, and even as fuel for cell energy production. PDAC cells metabolize glutamine through a non-canonical pathway in which transaminases play a crucial role. Whereas most cells use glutamate dehydrogenase (GDH-1) to convert glutamine-derived glutamate into alpha-ketoglutarate in the mitochondria to fuel the TCA cycle, PDAC relies on a distinct pathway in which glutamine-derived aspartate is transported into the cytoplasm where it can be converted into oxaloacetate by aspartate transaminase (i.e. glutamic-oxaloacetic transaminase [GOT-1]), then into malate, and finally into pyruvate. |
|
Formal Description Interaction-ID: 59866 |
|
| Comment | Conversion of malate to pyruvate by malic enzyme results in an increased NADPH/NADP+ ratio (nicotinamide adenine dinucleotide phosphate), providing the reducing power to maintain reduced glutathione pools to protect cells against oxidative damage. |
|
Formal Description Interaction-ID: 59867 |
|
| Drugbank entries | Show/Hide entries for ME1 |
| Comment | Conversion of malate to pyruvate by malic enzyme results in an increased NADPH/NADP+ ratio (nicotinamide adenine dinucleotide phosphate), providing the reducing power to maintain reduced glutathione pools to protect cells against oxidative damage. |
|
Formal Description Interaction-ID: 59868 |
|
| Drugbank entries | Show/Hide entries for ME1 |
| Comment | Conversion of malate to pyruvate by malic enzyme results in an increased NADPH/NADP+ ratio (nicotinamide adenine dinucleotide phosphate), providing the reducing power to maintain reduced glutathione pools to protect cells against oxidative damage. |
|
Formal Description Interaction-ID: 59869 |
gene/protein affects_activity of process |
| Drugbank entries | Show/Hide entries for ME1 |
| Comment | Low expression of GDH-1 and overexpression of glutaminase, GOT-1, and enzymes using glutamine as a nitrogen donor (cytidine triphosphate synthase, guanine monophosphate synthetase, asparagine synthetase) are characteristic features of Pancreatic ductal adenocarcinomas (PDAC). In these tumors, transcriptional reprogramming of key metabolic enzymes in the glutamine pathway (e.g. GDH-1, GOT1) is driven by KRAS or MYC oncogenes. Thus, more than an anaplerotic precursor for the TCA cycle, glutamine is necessary to sustain PDAC cell growth required for biomass synthesis and maintenance of the redox balance. |
|
Formal Description Interaction-ID: 59870 |
|
| Drugbank entries | Show/Hide entries for GLUD1 |
| Comment | Low expression of GDH-1 and overexpression of glutaminase, GOT-1, and enzymes using glutamine as a nitrogen donor (cytidine triphosphate synthase, guanine monophosphate synthetase, asparagine synthetase) are characteristic features of Pancreatic ductal adenocarcinomas (PDAC). In these tumors, transcriptional reprogramming of key metabolic enzymes in the glutamine pathway (e.g. GDH-1, GOT1) is driven by KRAS or MYC oncogenes. Thus, more than an anaplerotic precursor for the TCA cycle, glutamine is necessary to sustain PDAC cell growth required for biomass synthesis and maintenance of the redox balance. |
|
Formal Description Interaction-ID: 59871 |
|
| Drugbank entries | Show/Hide entries for GOT1 |
| Comment | Low expression of GDH-1 and overexpression of glutaminase, GOT-1, and enzymes using glutamine as a nitrogen donor (cytidine triphosphate synthase, guanine monophosphate synthetase, asparagine synthetase) are characteristic features of Pancreatic ductal adenocarcinomas (PDAC). In these tumors, transcriptional reprogramming of key metabolic enzymes in the glutamine pathway (e.g. GDH-1, GOT1) is driven by KRAS or MYC oncogenes. Thus, more than an anaplerotic precursor for the TCA cycle, glutamine is necessary to sustain PDAC cell growth required for biomass synthesis and maintenance of the redox balance. |
|
Formal Description Interaction-ID: 59872 |
|
| Drugbank entries | Show/Hide entries for CTPS |
| Comment | Low expression of GDH-1 and overexpression of glutaminase, GOT-1, and enzymes using glutamine as a nitrogen donor (cytidine triphosphate synthase, guanine monophosphate synthetase, asparagine synthetase) are characteristic features of Pancreatic ductal adenocarcinomas (PDAC). In these tumors, transcriptional reprogramming of key metabolic enzymes in the glutamine pathway (e.g. GDH-1, GOT1) is driven by KRAS or MYC oncogenes. Thus, more than an anaplerotic precursor for the TCA cycle, glutamine is necessary to sustain PDAC cell growth required for biomass synthesis and maintenance of the redox balance. |
|
Formal Description Interaction-ID: 59873 |
|
| Drugbank entries | Show/Hide entries for GMPS |
| Comment | Low expression of GDH-1 and overexpression of glutaminase, GOT-1, and enzymes using glutamine as a nitrogen donor (cytidine triphosphate synthase, guanine monophosphate synthetase, asparagine synthetase) are characteristic features of Pancreatic ductal adenocarcinomas (PDAC). In these tumors, transcriptional reprogramming of key metabolic enzymes in the glutamine pathway (e.g. GDH-1, GOT1) is driven by KRAS or MYC oncogenes. Thus, more than an anaplerotic precursor for the TCA cycle, glutamine is necessary to sustain PDAC cell growth required for biomass synthesis and maintenance of the redox balance. |
|
Formal Description Interaction-ID: 59874 |
|
| Drugbank entries | Show/Hide entries for ASNS |
| Comment | Low expression of GDH-1 and overexpression of glutaminase, GOT-1, and enzymes using glutamine as a nitrogen donor (cytidine triphosphate synthase, guanine monophosphate synthetase, asparagine synthetase) are characteristic features of Pancreatic ductal adenocarcinomas (PDAC). In these tumors, transcriptional reprogramming of key metabolic enzymes in the glutamine pathway (e.g. GDH-1, GOT1) is driven by KRAS or MYC oncogenes. Thus, more than an anaplerotic precursor for the TCA cycle, glutamine is necessary to sustain PDAC cell growth required for biomass synthesis and maintenance of the redox balance. |
|
Formal Description Interaction-ID: 59875 |
|
| Drugbank entries | Show/Hide entries for KRAS or GLUD1 |
| Comment | Low expression of GDH-1 and overexpression of glutaminase, GOT-1, and enzymes using glutamine as a nitrogen donor (cytidine triphosphate synthase, guanine monophosphate synthetase, asparagine synthetase) are characteristic features of Pancreatic ductal adenocarcinomas (PDAC). In these tumors, transcriptional reprogramming of key metabolic enzymes in the glutamine pathway (e.g. GDH-1, GOT1) is driven by KRAS or MYC oncogenes. Thus, more than an anaplerotic precursor for the TCA cycle, glutamine is necessary to sustain PDAC cell growth required for biomass synthesis and maintenance of the redox balance. |
|
Formal Description Interaction-ID: 59876 |
|
| Drugbank entries | Show/Hide entries for KRAS or GOT1 |
| Comment | Low expression of GDH-1 and overexpression of glutaminase, GOT-1, and enzymes using glutamine as a nitrogen donor (cytidine triphosphate synthase, guanine monophosphate synthetase, asparagine synthetase) are characteristic features of Pancreatic ductal adenocarcinomas (PDAC). In these tumors, transcriptional reprogramming of key metabolic enzymes in the glutamine pathway (e.g. GDH-1, GOT1) is driven by KRAS or MYC oncogenes. Thus, more than an anaplerotic precursor for the TCA cycle, glutamine is necessary to sustain PDAC cell growth required for biomass synthesis and maintenance of the redox balance. |
|
Formal Description Interaction-ID: 59877 |
|
| Drugbank entries | Show/Hide entries for GLUD1 |
| Comment | Low expression of GDH-1 and overexpression of glutaminase, GOT-1, and enzymes using glutamine as a nitrogen donor (cytidine triphosphate synthase, guanine monophosphate synthetase, asparagine synthetase) are characteristic features of Pancreatic ductal adenocarcinomas (PDAC). In these tumors, transcriptional reprogramming of key metabolic enzymes in the glutamine pathway (e.g. GDH-1, GOT1) is driven by KRAS or MYC oncogenes. Thus, more than an anaplerotic precursor for the TCA cycle, glutamine is necessary to sustain PDAC cell growth required for biomass synthesis and maintenance of the redox balance. |
|
Formal Description Interaction-ID: 59878 |
|
| Drugbank entries | Show/Hide entries for GOT1 |
| Comment | Glucose deprivation has been shown to induce the expression of asparagine synthetase (ASNS) probably through the unfolded-protein response (UPR) pathway as a means to protect cells from apoptosis. However, in contrast to normal pancreatic tissue that expresses high levels of ASNS, approximately half of PDAC cells express no or low ASNS levels. These tumors may thus harbor an intrinsic fragility to asparagine deprivation that may be exploited therapeutically by L-asparaginase therapy. |
|
Formal Description Interaction-ID: 59879 |
environment glucose deprivation increases_expression of gene/protein |
| Drugbank entries | Show/Hide entries for ASNS |
| Comment | The hexosamine biosynthetic pathway (HBP) is responsible for N-acetylglucosamine (GlcNAc) production for protein O-GlcNAc glycosylation. Glucosaminefructose-6-phosphate aminotransferase (GFPT) uses glutamine as a substrate to convert fructose-6-phosphate into glucosamine-6-phosphate, which is one of the precursors for UDP-GlcNAc synthesis and O-GlcNAc glycosylation. HBP activity thus depends on both glutamine as well as glucose (which is converted into fructose-6-phosphate). PDAC cells exhibit high levels of O-GlcNAc glycosylated proteins due to upregulation of GFPT1, GFPT2, and O-GlcNAc-transferase, and low levels of O-GlcNAcase, the enzyme catalyzing deglycosylation. |
|
Formal Description Interaction-ID: 59880 |
process hexosamine biosynthetic pathway increases_quantity of drug/chemical compound |
| Drugbank entries | Show/Hide entries for |
| Comment | The hexosamine biosynthetic pathway (HBP) is responsible for N-acetylglucosamine (GlcNAc) production for protein O-GlcNAc glycosylation. Glucosaminefructose-6-phosphate aminotransferase (GFPT) uses glutamine as a substrate to convert fructose-6-phosphate into glucosamine-6-phosphate, which is one of the precursors for UDP-GlcNAc synthesis and O-GlcNAc glycosylation. HBP activity thus depends on both glutamine as well as glucose (which is converted into fructose-6-phosphate). PDAC cells exhibit high levels of O-GlcNAc glycosylated proteins due to upregulation of GFPT1, GFPT2, and O-GlcNAc-transferase, and low levels of O-GlcNAcase, the enzyme catalyzing deglycosylation. |
|
Formal Description Interaction-ID: 59881 |
|
| Comment | The hexosamine biosynthetic pathway (HBP) is responsible for N-acetylglucosamine (GlcNAc) production for protein O-GlcNAc glycosylation. Glucosaminefructose-6-phosphate aminotransferase (GFPT) uses glutamine as a substrate to convert fructose-6-phosphate into glucosamine-6-phosphate, which is one of the precursors for UDP-GlcNAc synthesis and O-GlcNAc glycosylation. HBP activity thus depends on both glutamine as well as glucose (which is converted into fructose-6-phosphate). PDAC cells exhibit high levels of O-GlcNAc glycosylated proteins due to upregulation of GFPT1, GFPT2, and O-GlcNAc-transferase, and low levels of O-GlcNAcase, the enzyme catalyzing deglycosylation. |
|
Formal Description Interaction-ID: 59882 |
|
| Comment | The hexosamine biosynthetic pathway (HBP) is responsible for N-acetylglucosamine (GlcNAc) production for protein O-GlcNAc glycosylation. Glucosaminefructose-6-phosphate aminotransferase (GFPT) uses glutamine as a substrate to convert fructose-6-phosphate into glucosamine-6-phosphate, which is one of the precursors for UDP-GlcNAc synthesis and O-GlcNAc glycosylation. HBP activity thus depends on both glutamine as well as glucose (which is converted into fructose-6-phosphate). PDAC cells exhibit high levels of O-GlcNAc glycosylated proteins due to upregulation of GFPT1, GFPT2, and O-GlcNAc-transferase, and low levels of O-GlcNAcase, the enzyme catalyzing deglycosylation. |
|
Formal Description Interaction-ID: 59883 |
|
| Drugbank entries | Show/Hide entries for |
| Comment | The hexosamine biosynthetic pathway (HBP) is responsible for N-acetylglucosamine (GlcNAc) production for protein O-GlcNAc glycosylation. Glucosaminefructose-6-phosphate aminotransferase (GFPT) uses glutamine as a substrate to convert fructose-6-phosphate into glucosamine-6-phosphate, which is one of the precursors for UDP-GlcNAc synthesis and O-GlcNAc glycosylation. HBP activity thus depends on both glutamine as well as glucose (which is converted into fructose-6-phosphate). PDAC cells exhibit high levels of O-GlcNAc glycosylated proteins due to upregulation of GFPT1, GFPT2, and O-GlcNAc-transferase, and low levels of O-GlcNAcase, the enzyme catalyzing deglycosylation. |
|
Formal Description Interaction-ID: 59884 |
|
| Comment | The hexosamine biosynthetic pathway (HBP) is responsible for N-acetylglucosamine (GlcNAc) production for protein O-GlcNAc glycosylation. Glucosaminefructose-6-phosphate aminotransferase (GFPT) uses glutamine as a substrate to convert fructose-6-phosphate into glucosamine-6-phosphate, which is one of the precursors for UDP-GlcNAc synthesis and O-GlcNAc glycosylation. HBP activity thus depends on both glutamine as well as glucose (which is converted into fructose-6-phosphate). PDAC cells exhibit high levels of O-GlcNAc glycosylated proteins due to upregulation of GFPT1, GFPT2, and O-GlcNAc-transferase, and low levels of O-GlcNAcase, the enzyme catalyzing deglycosylation. |
|
Formal Description Interaction-ID: 59885 |
|
| Comment | The hexosamine biosynthetic pathway (HBP) is responsible for N-acetylglucosamine (GlcNAc) production for protein O-GlcNAc glycosylation. Glucosaminefructose-6-phosphate aminotransferase (GFPT) uses glutamine as a substrate to convert fructose-6-phosphate into glucosamine-6-phosphate, which is one of the precursors for UDP-GlcNAc synthesis and O-GlcNAc glycosylation. HBP activity thus depends on both glutamine as well as glucose (which is converted into fructose-6-phosphate). PDAC cells exhibit high levels of O-GlcNAc glycosylated proteins due to upregulation of GFPT1, GFPT2, and O-GlcNAc-transferase, and low levels of O-GlcNAcase, the enzyme catalyzing deglycosylation. |
|
Formal Description Interaction-ID: 59886 |
|
| Comment | The hexosamine biosynthetic pathway (HBP) is responsible for N-acetylglucosamine (GlcNAc) production for protein O-GlcNAc glycosylation. Glucosaminefructose-6-phosphate aminotransferase (GFPT) uses glutamine as a substrate to convert fructose-6-phosphate into glucosamine-6-phosphate, which is one of the precursors for UDP-GlcNAc synthesis and O-GlcNAc glycosylation. HBP activity thus depends on both glutamine as well as glucose (which is converted into fructose-6-phosphate). PDAC cells exhibit high levels of O-GlcNAc glycosylated proteins due to upregulation of GFPT1, GFPT2, and O-GlcNAc-transferase, and low levels of O-GlcNAcase, the enzyme catalyzing deglycosylation. |
|
Formal Description Interaction-ID: 59887 |
|
| Comment | The hexosamine biosynthetic pathway (HBP) is responsible for N-acetylglucosamine (GlcNAc) production for protein O-GlcNAc glycosylation. Glucosaminefructose-6-phosphate aminotransferase (GFPT) uses glutamine as a substrate to convert fructose-6-phosphate into glucosamine-6-phosphate, which is one of the precursors for UDP-GlcNAc synthesis and O-GlcNAc glycosylation. HBP activity thus depends on both glutamine as well as glucose (which is converted into fructose-6-phosphate). PDAC cells exhibit high levels of O-GlcNAc glycosylated proteins due to upregulation of GFPT1, GFPT2, and O-GlcNAc-transferase, and low levels of O-GlcNAcase, the enzyme catalyzing deglycosylation. |
|
Formal Description Interaction-ID: 59888 |
|
| Comment | Increased glucose and glutamine uptake and KRAS-dependent upregulation of GFPT, the rate-limiting enzyme in this process, result in increased hexosamine biosynthetic pathway (HBP) activity in pancreatic ductal adenocarcinomas (PDAC), which has been associated with tumor invasion and metastasis. |
|
Formal Description Interaction-ID: 59889 |
|
| Comment | Increased glucose and glutamine uptake and KRAS-dependent upregulation of GFPT, the rate-limiting enzyme in this process, result in increased hexosamine biosynthetic pathway (HBP) activity in pancreatic ductal adenocarcinomas (PDAC), which has been associated with tumor invasion and metastasis. |
|
Formal Description Interaction-ID: 59890 |
process hexosamine biosynthetic pathway increases_activity of process tumor invasion |
| Comment | Increased glucose and glutamine uptake and KRAS-dependent upregulation of GFPT, the rate-limiting enzyme in this process, result in increased hexosamine biosynthetic pathway (HBP) activity in pancreatic ductal adenocarcinomas (PDAC), which has been associated with tumor invasion and metastasis. |
|
Formal Description Interaction-ID: 59891 |
process hexosamine biosynthetic pathway increases_activity of process tumor invasion |
| Comment | Increased glucose and glutamine uptake and KRAS-dependent upregulation of GFPT, the rate-limiting enzyme in this process, result in increased hexosamine biosynthetic pathway (HBP) activity in pancreatic ductal adenocarcinomas (PDAC), which has been associated with tumor invasion and metastasis. |
|
Formal Description Interaction-ID: 59892 |
process hexosamine biosynthetic pathway increases_activity of phenotype |
| Comment | O-GlcNAc glycosylation can redirect glucose to the pentose phosphate pathway (PPP) by inhibiting phosphofructokinase-1 and stabilizes key transcription factors such as p53, c-Myc or beta-catenin. It also promotes aneuploidy and participates in cancer cell phenotype by enhancing insulin, TGF-beta, and FGF pathway activity through transcriptional and epigenetic mechanisms. |
|
Formal Description Interaction-ID: 59893 |
|
| Comment | O-GlcNAc glycosylation can redirect glucose to the pentose phosphate pathway (PPP) by inhibiting phosphofructokinase-1 and stabilizes key transcription factors such as p53, c-Myc or beta-catenin. It also promotes aneuploidy and participates in cancer cell phenotype by enhancing insulin, TGF-beta, and FGF pathway activity through transcriptional and epigenetic mechanisms. |
|
Formal Description Interaction-ID: 59894 |
|
| Comment | O-GlcNAc glycosylation can redirect glucose to the pentose phosphate pathway (PPP) by inhibiting phosphofructokinase-1 and stabilizes key transcription factors such as p53, c-Myc or beta-catenin. It also promotes aneuploidy and participates in cancer cell phenotype by enhancing insulin, TGF-beta, and FGF pathway activity through transcriptional and epigenetic mechanisms. |
|
Formal Description Interaction-ID: 59895 |
|
| Drugbank entries | Show/Hide entries for TP53 |
| Comment | O-GlcNAc glycosylation can redirect glucose to the pentose phosphate pathway (PPP) by inhibiting phosphofructokinase-1 and stabilizes key transcription factors such as p53, c-Myc or beta-catenin. It also promotes aneuploidy and participates in cancer cell phenotype by enhancing insulin, TGF-beta, and FGF pathway activity through transcriptional and epigenetic mechanisms. |
|
Formal Description Interaction-ID: 59896 |
|
| Comment | O-GlcNAc glycosylation can redirect glucose to the pentose phosphate pathway (PPP) by inhibiting phosphofructokinase-1 and stabilizes key transcription factors such as p53, c-Myc or beta-catenin. It also promotes aneuploidy and participates in cancer cell phenotype by enhancing insulin, TGF-beta, and FGF pathway activity through transcriptional and epigenetic mechanisms. |
|
Formal Description Interaction-ID: 59897 |
|
| Drugbank entries | Show/Hide entries for CTNNB1 |
| Comment | O-GlcNAc glycosylation can redirect glucose to the pentose phosphate pathway (PPP) by inhibiting phosphofructokinase-1 and stabilizes key transcription factors such as p53, c-Myc or beta-catenin. It also promotes aneuploidy and participates in cancer cell phenotype by enhancing insulin, TGF-beta, and FGF pathway activity through transcriptional and epigenetic mechanisms. |
|
Formal Description Interaction-ID: 59898 |
|
| Comment | O-GlcNAc glycosylation can redirect glucose to the pentose phosphate pathway (PPP) by inhibiting phosphofructokinase-1 and stabilizes key transcription factors such as p53, c-Myc or beta-catenin. It also promotes aneuploidy and participates in cancer cell phenotype by enhancing insulin, TGF-beta, and FGF pathway activity through transcriptional and epigenetic mechanisms. |
|
Formal Description Interaction-ID: 59899 |
|
| Drugbank entries | Show/Hide entries for TGFB1 |
| Comment | O-GlcNAc glycosylation can redirect glucose to the pentose phosphate pathway (PPP) by inhibiting phosphofructokinase-1 and stabilizes key transcription factors such as p53, c-Myc or beta-catenin. It also promotes aneuploidy and participates in cancer cell phenotype by enhancing insulin, TGF-beta, and FGF pathway activity through transcriptional and epigenetic mechanisms. |
|
Formal Description Interaction-ID: 59900 |
process increases_activity of |
| Comment | The hexosamine biosynthetic pathway (HBP) can modulate tyrosine kinase receptor (TKR) signaling. HBP inhibition using tunicamycin (a nucleoside antibiotic that blocks GlcNAc-1-phosphotransferase) in PDAC, resulted in decreased protein levels and membrane expression of several TKR such as EGFR (epidermal growth factor receptor), ErbB2, ErbB3, and IGFR (insulin-like growth factor receptor). Of note, glucose deprivation reduces HBP activity, which decreases protein glycosylation and induces UPR-dependent cell death. The metabolic switch induced by HBP is thus at the crossroads between growth factor survival and microenvironment signaling and may represent an innovative approach in cancer therapy. |
|
Formal Description Interaction-ID: 59901 |
process hexosamine biosynthetic pathway affects_activity of |
| Comment | The hexosamine biosynthetic pathway (HBP) can modulate tyrosine kinase receptor (TKR) signaling. HBP inhibition using tunicamycin (a nucleoside antibiotic that blocks GlcNAc-1-phosphotransferase) in PDAC, resulted in decreased protein levels and membrane expression of several TKR such as EGFR (epidermal growth factor receptor), ErbB2, ErbB3, and IGFR (insulin-like growth factor receptor). Of note, glucose deprivation reduces HBP activity, which decreases protein glycosylation and induces UPR-dependent cell death. The metabolic switch induced by HBP is thus at the crossroads between growth factor survival and microenvironment signaling and may represent an innovative approach in cancer therapy. |
|
Formal Description Interaction-ID: 59902 |
|
| Drugbank entries | Show/Hide entries for EGFR |
| Comment | The hexosamine biosynthetic pathway (HBP) can modulate tyrosine kinase receptor (TKR) signaling. HBP inhibition using tunicamycin (a nucleoside antibiotic that blocks GlcNAc-1-phosphotransferase) in PDAC, resulted in decreased protein levels and membrane expression of several TKR such as EGFR (epidermal growth factor receptor), ErbB2, ErbB3, and IGFR (insulin-like growth factor receptor). Of note, glucose deprivation reduces HBP activity, which decreases protein glycosylation and induces UPR-dependent cell death. The metabolic switch induced by HBP is thus at the crossroads between growth factor survival and microenvironment signaling and may represent an innovative approach in cancer therapy. |
|
Formal Description Interaction-ID: 59903 |
|
| Drugbank entries | Show/Hide entries for ERBB2 |
| Comment | The hexosamine biosynthetic pathway (HBP) can modulate tyrosine kinase receptor (TKR) signaling. HBP inhibition using tunicamycin (a nucleoside antibiotic that blocks GlcNAc-1-phosphotransferase) in PDAC, resulted in decreased protein levels and membrane expression of several TKR such as EGFR (epidermal growth factor receptor), ErbB2, ErbB3, and IGFR (insulin-like growth factor receptor). Of note, glucose deprivation reduces HBP activity, which decreases protein glycosylation and induces UPR-dependent cell death. The metabolic switch induced by HBP is thus at the crossroads between growth factor survival and microenvironment signaling and may represent an innovative approach in cancer therapy. |
|
Formal Description Interaction-ID: 59904 |
|
| Comment | The hexosamine biosynthetic pathway (HBP) can modulate tyrosine kinase receptor (TKR) signaling. HBP inhibition using tunicamycin (a nucleoside antibiotic that blocks GlcNAc-1-phosphotransferase) in PDAC, resulted in decreased protein levels and membrane expression of several TKR such as EGFR (epidermal growth factor receptor), ErbB2, ErbB3, and IGFR (insulin-like growth factor receptor). Of note, glucose deprivation reduces HBP activity, which decreases protein glycosylation and induces UPR-dependent cell death. The metabolic switch induced by HBP is thus at the crossroads between growth factor survival and microenvironment signaling and may represent an innovative approach in cancer therapy. |
|
Formal Description Interaction-ID: 59905 |
process hexosamine biosynthetic pathway affects_activity of |
| Comment | The hexosamine biosynthetic pathway (HBP) can modulate tyrosine kinase receptor (TKR) signaling. HBP inhibition using tunicamycin (a nucleoside antibiotic that blocks GlcNAc-1-phosphotransferase) in PDAC, resulted in decreased protein levels and membrane expression of several TKR such as EGFR (epidermal growth factor receptor), ErbB2, ErbB3, and IGFR (insulin-like growth factor receptor). Of note, glucose deprivation reduces HBP activity, which decreases protein glycosylation and induces UPR-dependent cell death. The metabolic switch induced by HBP is thus at the crossroads between growth factor survival and microenvironment signaling and may represent an innovative approach in cancer therapy. |
|
Formal Description Interaction-ID: 59906 |
environment glucose deprivation decreases_activity of process hexosamine biosynthetic pathway |
| Comment | Fatty acid (FA) synthesis occurs at a low level in most normal tissues, with the exception of liver and adipose tissues. However in cancer cells, FA are synthesized at high levels and undergo esterification, mainly providing phospholipids for membrane formation. PDAC cells overexpress enzymes involved in FA and cholesterol synthesis such as FA synthase (FAS) and ATP citrate lyase, while levels of several enzymes involved in FA beta-oxidation in mitochondria are reduced. FA synthesis requires NADPH that is produced in PDAC cells either by the KRAS-activated pentose phosphate pathway (PPP) or by malic enzyme during glutaminolysis. Overexpression of FAS in PDAC is associated with poor prognosis. |
|
Formal Description Interaction-ID: 59907 |
|
| Comment | Fatty acid (FA) synthesis occurs at a low level in most normal tissues, with the exception of liver and adipose tissues. However in cancer cells, FA are synthesized at high levels and undergo esterification, mainly providing phospholipids for membrane formation. PDAC cells overexpress enzymes involved in FA and cholesterol synthesis such as FA synthase (FAS) and ATP citrate lyase, while levels of several enzymes involved in FA beta-oxidation in mitochondria are reduced. FA synthesis requires NADPH that is produced in PDAC cells either by the KRAS-activated pentose phosphate pathway (PPP) or by malic enzyme during glutaminolysis. Overexpression of FAS in PDAC is associated with poor prognosis. |
|
Formal Description Interaction-ID: 59908 |
|
| Drugbank entries | Show/Hide entries for FASN |
| Comment | Fatty acid (FA) synthesis occurs at a low level in most normal tissues, with the exception of liver and adipose tissues. However in cancer cells, FA are synthesized at high levels and undergo esterification, mainly providing phospholipids for membrane formation. PDAC cells overexpress enzymes involved in FA and cholesterol synthesis such as FA synthase (FAS) and ATP citrate lyase, while levels of several enzymes involved in FA beta-oxidation in mitochondria are reduced. FA synthesis requires NADPH that is produced in PDAC cells either by the KRAS-activated pentose phosphate pathway (PPP) or by malic enzyme during glutaminolysis. Overexpression of FAS in PDAC is associated with poor prognosis. |
|
Formal Description Interaction-ID: 59909 |
|
| Comment | Fatty acid (FA) synthesis occurs at a low level in most normal tissues, with the exception of liver and adipose tissues. However in cancer cells, FA are synthesized at high levels and undergo esterification, mainly providing phospholipids for membrane formation. PDAC cells overexpress enzymes involved in FA and cholesterol synthesis such as FA synthase (FAS) and ATP citrate lyase, while levels of several enzymes involved in FA beta-oxidation in mitochondria are reduced. FA synthesis requires NADPH that is produced in PDAC cells either by the KRAS-activated pentose phosphate pathway (PPP) or by malic enzyme during glutaminolysis. Overexpression of FAS in PDAC is associated with poor prognosis. |
|
Formal Description Interaction-ID: 59910 |
|
| Comment | The oncogenic potential of fatty acid synthase (FAS) exploits several mechanisms; FAS expression is strongly induced by hypoxia, the PI3K/AKT/mTOR pathway through activation of SREBP1c transcription factor, and by microenvironment acidification through epigenetic modifications of the FAS promoter. |
|
Formal Description Interaction-ID: 59911 |
|
| Drugbank entries | Show/Hide entries for FASN |
| Comment | The oncogenic potential of fatty acid synthase (FAS) exploits several mechanisms; FAS expression is strongly induced by hypoxia, the PI3K/AKT/mTOR pathway through activation of SREBP1c transcription factor, and by microenvironment acidification through epigenetic modifications of the FAS promoter. |
|
Formal Description Interaction-ID: 59912 |
|
| Drugbank entries | Show/Hide entries for FASN |
| Comment | The oncogenic potential of fatty acid synthase (FAS) exploits several mechanisms; FAS expression is strongly induced by hypoxia, the PI3K/AKT/mTOR pathway through activation of SREBP1c transcription factor, and by microenvironment acidification through epigenetic modifications of the FAS promoter. |
|
Formal Description Interaction-ID: 59913 |
|
| Drugbank entries | Show/Hide entries for FASN |
| Comment | The oncogenic potential of fatty acid synthase (FAS) exploits several mechanisms; FAS expression is strongly induced by hypoxia, the PI3K/AKT/mTOR pathway through activation of SREBP1c transcription factor, and by microenvironment acidification through epigenetic modifications of the FAS promoter. |
|
Formal Description Interaction-ID: 59914 |
|
| Drugbank entries | Show/Hide entries for FASN |
| Comment | The oncogenic potential of fatty acid synthase (FAS) exploits several mechanisms; FAS expression is strongly induced by hypoxia, the PI3K/AKT/mTOR pathway through activation of SREBP1c transcription factor, and by microenvironment acidification through epigenetic modifications of the FAS promoter. |
|
Formal Description Interaction-ID: 59915 |
|
| Comment | Lipoprotein catabolism and cholesterol synthesis pathways are enriched in PDAC, compared with nonmalignant pancreas. Cholesterol uptake disruption through shRNA silencing of LDLR inhibit proliferation and ERK1/2 pathway activation of PDAC cells. |
|
Formal Description Interaction-ID: 59916 |
|
| Comment | Lipoprotein catabolism and cholesterol synthesis pathways are enriched in PDAC, compared with nonmalignant pancreas. Cholesterol uptake disruption through shRNA silencing of LDLR inhibit proliferation and ERK1/2 pathway activation of PDAC cells. |
|
Formal Description Interaction-ID: 59917 |
|
| Comment | Lipoprotein catabolism and cholesterol synthesis pathways are enriched in PDAC, compared with nonmalignant pancreas. Cholesterol uptake disruption through shRNA silencing of LDLR inhibit proliferation and ERK1/2 pathway activation of PDAC cells. |
|
Formal Description Interaction-ID: 59918 |
|
| Comment | Lipoprotein catabolism and cholesterol synthesis pathways are enriched in PDAC, compared with nonmalignant pancreas. Cholesterol uptake disruption through shRNA silencing of LDLR inhibit proliferation and ERK1/2 pathway activation of PDAC cells. |
|
Formal Description Interaction-ID: 59919 |
|
| Comment | Pyruvate kinase controls the penultimate step of glycolysis, catalyzing the production of pyruvate and ATP from phosphoenopyruvate (PEP) and adenosine 5'-diphosphate (ADP), putting PKM2 at the core of the glycolytic switch in cancer cells. This enzyme has several isoforms (M1, M2, L, R), with PKM1 and PKM2 resulting from an alternative splicing of the same pre-mRNA. PKM2 is found in several tissues (liver, lung, pancreatic islets, and retina) and is preferentially expressed over PKM1 in cancer cells through cMyc-dependent splicing modulation. |
|
Formal Description Interaction-ID: 59920 |
|
| Drugbank entries | Show/Hide entries for PKM2 or Phosphoenolpyruvate |
| Comment | Pyruvate kinase controls the penultimate step of glycolysis, catalyzing the production of pyruvate and ATP from phosphoenopyruvate (PEP) and adenosine 5'-diphosphate (ADP), putting PKM2 at the core of the glycolytic switch in cancer cells. This enzyme has several isoforms (M1, M2, L, R), with PKM1 and PKM2 resulting from an alternative splicing of the same pre-mRNA. PKM2 is found in several tissues (liver, lung, pancreatic islets, and retina) and is preferentially expressed over PKM1 in cancer cells through cMyc-dependent splicing modulation. |
|
Formal Description Interaction-ID: 59921 |
|
| Drugbank entries | Show/Hide entries for PKM2 |
| Comment | Pyruvate kinase controls the penultimate step of glycolysis, catalyzing the production of pyruvate and ATP from phosphoenopyruvate (PEP) and adenosine 5'-diphosphate (ADP), putting PKM2 at the core of the glycolytic switch in cancer cells. This enzyme has several isoforms (M1, M2, L, R), with PKM1 and PKM2 resulting from an alternative splicing of the same pre-mRNA. PKM2 is found in several tissues (liver, lung, pancreatic islets, and retina) and is preferentially expressed over PKM1 in cancer cells through cMyc-dependent splicing modulation. |
|
Formal Description Interaction-ID: 59922 |
|
| Drugbank entries | Show/Hide entries for PKM2 |
| Comment | Pyruvate kinase controls the penultimate step of glycolysis, catalyzing the production of pyruvate and ATP from phosphoenopyruvate (PEP) and adenosine 5'-diphosphate (ADP), putting PKM2 at the core of the glycolytic switch in cancer cells. This enzyme has several isoforms (M1, M2, L, R), with PKM1 and PKM2 resulting from an alternative splicing of the same pre-mRNA. PKM2 is found in several tissues (liver, lung, pancreatic islets, and retina) and is preferentially expressed over PKM1 in cancer cells through cMyc-dependent splicing modulation. |
|
Formal Description Interaction-ID: 59923 |
|
| Drugbank entries | Show/Hide entries for PKM2 |
| Comment | Pyruvate kinase controls the penultimate step of glycolysis, catalyzing the production of pyruvate and ATP from phosphoenopyruvate (PEP) and adenosine 5'-diphosphate (ADP), putting PKM2 at the core of the glycolytic switch in cancer cells. This enzyme has several isoforms (M1, M2, L, R), with PKM1 and PKM2 resulting from an alternative splicing of the same pre-mRNA. PKM2 is found in several tissues (liver, lung, pancreatic islets, and retina) and is preferentially expressed over PKM1 in cancer cells through cMyc-dependent splicing modulation. |
|
Formal Description Interaction-ID: 59924 |
|
| Drugbank entries | Show/Hide entries for PKM2 |
| Comment | PKM2 is present as either active tetramers or inactive dimers. In cancer cells, it is predominantly found in dimers with low activity. Active tetramers induce OXPHOS whereas inactive dimers favor cytoplasmic conversion of pyruvate into lactate by LDH-A. The low glycolytic activity of PKM2 dimers allows upstream glycolytic metabolite accumulation and their redirection towards anabolic pathways. |
|
Formal Description Interaction-ID: 59925 |
mRNA/protein variant increases_activity of process |
| Drugbank entries | Show/Hide entries for PKM2 |
| Comment | PKM2 is present as either active tetramers or inactive dimers. In cancer cells, it is predominantly found in dimers with low activity. Active tetramers induce OXPHOS whereas inactive dimers favor cytoplasmic conversion of pyruvate into lactate by LDH-A. The low glycolytic activity of PKM2 dimers allows upstream glycolytic metabolite accumulation and their redirection towards anabolic pathways. |
|
Formal Description Interaction-ID: 59926 |
|
| Drugbank entries | Show/Hide entries for PKM2 |
| Comment | Monomeric PKM2 can translocate into the nucleus and acts as a co-transcription factor. Activation of the EGFR pathway promotes PKM2 nuclear translocation via EGFR-activated ERK1/2 which directly binds and phosphorylates PKM2 on Ser37, resulting in its nuclear translocation and activation, without any effect on PKM1. Through a positive feedback loop, PKM2 binding to succinyl-5-aminoimidazole-4-carboxamide-1- ribose-5'-phosphate (SAICAR), an intermediate of the de novo purine nucleotide biosynthesis that is abundant in proliferative cells, leads to phosphorylation and activation of ERK1/2. In the nucleus, PKM2 interacts with nuclear HIF1-alpha and p300 to induce transcription of hypoxia-responsive genes (e.g. anaerobic glycolysis genes). |
|
Formal Description Interaction-ID: 59927 |
increases_activity of process |
| Comment | Monomeric PKM2 can translocate into the nucleus and acts as a co-transcription factor. Activation of the EGFR pathway promotes PKM2 nuclear translocation via EGFR-activated ERK1/2 which directly binds and phosphorylates PKM2 on Ser37, resulting in its nuclear translocation and activation, without any effect on PKM1. Through a positive feedback loop, PKM2 binding to succinyl-5-aminoimidazole-4-carboxamide-1- ribose-5'-phosphate (SAICAR), an intermediate of the de novo purine nucleotide biosynthesis that is abundant in proliferative cells, leads to phosphorylation and activation of ERK1/2. In the nucleus, PKM2 interacts with nuclear HIF1-alpha and p300 to induce transcription of hypoxia-responsive genes (e.g. anaerobic glycolysis genes). |
|
Formal Description Interaction-ID: 59928 |
|
| Drugbank entries | Show/Hide entries for PKM2 |
| Comment | Monomeric PKM2 can translocate into the nucleus and acts as a co-transcription factor. Activation of the EGFR pathway promotes PKM2 nuclear translocation via EGFR-activated ERK1/2 which directly binds and phosphorylates PKM2 on Ser37, resulting in its nuclear translocation and activation, without any effect on PKM1. Through a positive feedback loop, PKM2 binding to succinyl-5-aminoimidazole-4-carboxamide-1- ribose-5'-phosphate (SAICAR), an intermediate of the de novo purine nucleotide biosynthesis that is abundant in proliferative cells, leads to phosphorylation and activation of ERK1/2. In the nucleus, PKM2 interacts with nuclear HIF1-alpha and p300 to induce transcription of hypoxia-responsive genes (e.g. anaerobic glycolysis genes). |
|
Formal Description Interaction-ID: 59929 |
|
| Comment | PKM2 also binds to beta-catenin and promotes expression of pro-proliferative MYC and CCDN1 genes. In addition, PKM2 interacts with STAT3 and histone H3 whose phosphorylation on threonine 11 depends on EGFR activation and is required for the dissociation of HDAC3 from the CCND1 and MYC promoter regions. |
|
Formal Description Interaction-ID: 59930 |
|
| Drugbank entries | Show/Hide entries for PKM2 or CTNNB1 |
| Comment | PKM2 also binds to beta-catenin and promotes expression of pro-proliferative MYC and CCDN1 genes. In addition, PKM2 interacts with STAT3 and histone H3 whose phosphorylation on threonine 11 depends on EGFR activation and is required for the dissociation of HDAC3 from the CCND1 and MYC promoter regions. |
|
Formal Description Interaction-ID: 59931 |
|
| Drugbank entries | Show/Hide entries for PKM2 |
| Comment | PKM2 also binds to beta-catenin and promotes expression of pro-proliferative MYC and CCDN1 genes. In addition, PKM2 interacts with STAT3 and histone H3 whose phosphorylation on threonine 11 depends on EGFR activation and is required for the dissociation of HDAC3 from the CCND1 and MYC promoter regions. |
|
Formal Description Interaction-ID: 59932 |
|
| Drugbank entries | Show/Hide entries for PKM2 or CCND1 |
| Comment | PKM2 also binds to beta-catenin and promotes expression of pro-proliferative MYC and CCDN1 genes. In addition, PKM2 interacts with STAT3 and histone H3 whose phosphorylation on threonine 11 depends on EGFR activation and is required for the dissociation of HDAC3 from the CCND1 and MYC promoter regions. |
|
Formal Description Interaction-ID: 59933 |
|
| Drugbank entries | Show/Hide entries for PKM2 |
| Comment | PKM2 also binds to beta-catenin and promotes expression of pro-proliferative MYC and CCDN1 genes. In addition, PKM2 interacts with STAT3 and histone H3 whose phosphorylation on threonine 11 depends on EGFR activation and is required for the dissociation of HDAC3 from the CCND1 and MYC promoter regions. |
|
Formal Description Interaction-ID: 59934 |
|
| Drugbank entries | Show/Hide entries for PKM2 |
| Comment | Lactate dehydrogenase (LDH) controls the rate-limiting final step of glycolysis, converting pyruvate into lactate in the cytoplasm. LDH activity is not required in normal tissues under normoxic conditions. The two LDH isoforms (LDH-A and -B) can be combined as five different tetramers (LDH-1‚Äď5). LDH-A is predominantly expressed in the liver and muscles and LDH-B in the myocardia. LDH-5 is composed of four LDH-A units which is overexpressed in many cancers including PDAC as a result of post-translational or transcriptional c-Myc, K-Ras, HIF-1alpha, and FOXM1 (for¬≠khead box protein M1) dependent regulation, and is associated with poor prognosis. |
|
Formal Description Interaction-ID: 59935 |
|
| Drugbank entries | Show/Hide entries for LDHA |
| Comment | Lactate dehydrogenase (LDH) controls the rate-limiting final step of glycolysis, converting pyruvate into lactate in the cytoplasm. LDH activity is not required in normal tissues under normoxic conditions. The two LDH isoforms (LDH-A and -B) can be combined as five different tetramers (LDH-1‚Äď5). LDH-A is predominantly expressed in the liver and muscles and LDH-B in the myocardia. LDH-5 is composed of four LDH-A units which is overexpressed in many cancers including PDAC as a result of post-translational or transcriptional c-Myc, K-Ras, HIF-1alpha, and FOXM1 (for¬≠khead box protein M1) dependent regulation, and is associated with poor prognosis. |
|
Formal Description Interaction-ID: 59936 |
|
| Drugbank entries | Show/Hide entries for LDHA |
| Comment | Lactate dehydrogenase (LDH) controls the rate-limiting final step of glycolysis, converting pyruvate into lactate in the cytoplasm. LDH activity is not required in normal tissues under normoxic conditions. The two LDH isoforms (LDH-A and -B) can be combined as five different tetramers (LDH-1‚Äď5). LDH-A is predominantly expressed in the liver and muscles and LDH-B in the myocardia. LDH-5 is composed of four LDH-A units which is overexpressed in many cancers including PDAC as a result of post-translational or transcriptional c-Myc, K-Ras, HIF-1alpha, and FOXM1 (for¬≠khead box protein M1) dependent regulation, and is associated with poor prognosis. |
|
Formal Description Interaction-ID: 59937 |
|
| Drugbank entries | Show/Hide entries for KRAS or LDHA |
| Comment | Lactate dehydrogenase (LDH) controls the rate-limiting final step of glycolysis, converting pyruvate into lactate in the cytoplasm. LDH activity is not required in normal tissues under normoxic conditions. The two LDH isoforms (LDH-A and -B) can be combined as five different tetramers (LDH-1‚Äď5). LDH-A is predominantly expressed in the liver and muscles and LDH-B in the myocardia. LDH-5 is composed of four LDH-A units which is overexpressed in many cancers including PDAC as a result of post-translational or transcriptional c-Myc, K-Ras, HIF-1alpha, and FOXM1 (for¬≠khead box protein M1) dependent regulation, and is associated with poor prognosis. |
|
Formal Description Interaction-ID: 59938 |
|
| Drugbank entries | Show/Hide entries for HIF1A or LDHA |
| Comment | Lactate dehydrogenase (LDH) controls the rate-limiting final step of glycolysis, converting pyruvate into lactate in the cytoplasm. LDH activity is not required in normal tissues under normoxic conditions. The two LDH isoforms (LDH-A and -B) can be combined as five different tetramers (LDH-1‚Äď5). LDH-A is predominantly expressed in the liver and muscles and LDH-B in the myocardia. LDH-5 is composed of four LDH-A units which is overexpressed in many cancers including PDAC as a result of post-translational or transcriptional c-Myc, K-Ras, HIF-1alpha, and FOXM1 (for¬≠khead box protein M1) dependent regulation, and is associated with poor prognosis. |
|
Formal Description Interaction-ID: 59939 |
|
| Drugbank entries | Show/Hide entries for LDHA |
| Comment | Two widely used drugs, metformin and statins, provide evidence that targeting lipid metabolism in cancer may have therapeutic efficacy. Metformin has antitumor effects in preclinical PDAC models, notably by inhibiting de novo FA synthesis via downregulation of Sp transcription factors that reduce FAS expression. |
|
Formal Description Interaction-ID: 59940 |
|
| Drugbank entries | Show/Hide entries for Metformin |
| Comment | Two widely used drugs, metformin and statins, provide evidence that targeting lipid metabolism in cancer may have therapeutic efficacy. Metformin has antitumor effects in preclinical PDAC models, notably by inhibiting de novo FA synthesis via downregulation of Sp transcription factors that reduce FAS expression. |
|
Formal Description Interaction-ID: 59941 |
|
| Drugbank entries | Show/Hide entries for Metformin or FASN |
| Comment | In in vitro and in vivo models, metformin was shown to impair proliferation and tumorigenicity of PDAC and cancer stem cells. |
|
Formal Description Interaction-ID: 59942 |
|
| Drugbank entries | Show/Hide entries for Metformin |
| Comment | Metformin inhibits OXPHOS (mitochondrial complex I), TCA cycle anaplerosis, and de novo FA palmitate synthesis from glucose-derived acetyl-CoA. Thus, metformin may contribute to limit cell membrane synthesis. With cholesterol and FA de novo synthesis inhibited, glucose metabolism is channeled towards lactate production, which is consistent with one of the observed side effects, lactic acidosis. In a stem cell-enriching culture model, metformin exposure significantly decreased mitochondrial transmembrane potential and increased mitochondrial ROS production. However, its effects on ROS production are controversial. |
|
Formal Description Interaction-ID: 59943 |
|
| Drugbank entries | Show/Hide entries for Metformin |
| Comment | Metformin inhibits OXPHOS (mitochondrial complex I), TCA cycle anaplerosis, and de novo FA palmitate synthesis from glucose-derived acetyl-CoA. Thus, metformin may contribute to limit cell membrane synthesis. With cholesterol and FA de novo synthesis inhibited, glucose metabolism is channeled towards lactate production, which is consistent with one of the observed side effects, lactic acidosis. In a stem cell-enriching culture model, metformin exposure significantly decreased mitochondrial transmembrane potential and increased mitochondrial ROS production. However, its effects on ROS production are controversial. |
|
Formal Description Interaction-ID: 59944 |
drug/chemical compound decreases_activity of complex/PPI Mitochondrial respiratory chain complex I |
| Drugbank entries | Show/Hide entries for Metformin |
| Comment | Metformin inhibits OXPHOS (mitochondrial complex I), TCA cycle anaplerosis, and de novo FA palmitate synthesis from glucose-derived acetyl-CoA. Thus, metformin may contribute to limit cell membrane synthesis. With cholesterol and FA de novo synthesis inhibited, glucose metabolism is channeled towards lactate production, which is consistent with one of the observed side effects, lactic acidosis. In a stem cell-enriching culture model, metformin exposure significantly decreased mitochondrial transmembrane potential and increased mitochondrial ROS production. However, its effects on ROS production are controversial. |
|
Formal Description Interaction-ID: 59945 |
|
| Drugbank entries | Show/Hide entries for Metformin |
| Comment | Metformin inhibits OXPHOS (mitochondrial complex I), TCA cycle anaplerosis, and de novo FA palmitate synthesis from glucose-derived acetyl-CoA. Thus, metformin may contribute to limit cell membrane synthesis. With cholesterol and FA de novo synthesis inhibited, glucose metabolism is channeled towards lactate production, which is consistent with one of the observed side effects, lactic acidosis. In a stem cell-enriching culture model, metformin exposure significantly decreased mitochondrial transmembrane potential and increased mitochondrial ROS production. However, its effects on ROS production are controversial. |
|
Formal Description Interaction-ID: 59946 |
drug/chemical compound increases_activity of phenotype lactic acidosis |
| Drugbank entries | Show/Hide entries for Metformin |
| Comment | Metformin may also exert an antitumor effect by inhibiting the mTOR pathway, as suggested by its association with reduced phospho-mTOR and phospho-p70S6K levels, independently of AKT inhibition. Metformin activates AMPK, which negatively regulates mTORC1. |
|
Formal Description Interaction-ID: 59947 |
|
| Drugbank entries | Show/Hide entries for Metformin |
| Comment | Metformin may also exert an antitumor effect by inhibiting the mTOR pathway, as suggested by its association with reduced phospho-mTOR and phospho-p70S6K levels, independently of AKT inhibition. Metformin activates AMPK, which negatively regulates mTORC1. |
|
Formal Description Interaction-ID: 59948 |
|
| Drugbank entries | Show/Hide entries for Metformin |
| Comment | Metformin may also exert an antitumor effect by inhibiting the mTOR pathway, as suggested by its association with reduced phospho-mTOR and phospho-p70S6K levels, independently of AKT inhibition. Metformin activates AMPK, which negatively regulates mTORC1. |
|
Formal Description Interaction-ID: 59949 |
|