{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Golinska MA"],"funding":["Cancer Research UK"],"pagination":["3595"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC9688062"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["11(22)"],"pubmed_abstract":["The HIF-1 and HIF-2 (HIF1/2) hypoxia responses are frequently upregulated in cancers, and HIF1/2 inhibitors are being developed as anticancer drugs. How could cancers resist anti-HIF1/2 therapy? We studied metabolic and molecular adaptations of HIF-1β-deficient Hepa-1c4, a hepatoma model lacking HIF1/2 signalling, which mimics a cancer treated by a totally effective anti-HIF1/2 agent. [1,2-<sup>13</sup>C<sub>2</sub>]-D-glucose metabolism was measured by SiDMAP metabolic profiling, gene expression by TaqMan, and metabolite concentrations by <sup>1</sup>H MRS. HIF-1β-deficient Hepa-1c4 responded to hypoxia by increasing glucose uptake and lactate production. They showed higher glutamate, pyruvate dehydrogenase, citrate shuttle, and malonyl-CoA fluxes than normal Hepa-1 cells, whereas pyruvate carboxylase, TCA, and anaplerotic fluxes decreased. Hypoxic HIF-1β-deficient Hepa-1c4 cells increased expression of PGC-1α, phospho-p38 MAPK, and PPARα, suggesting AMPK pathway activation to survive hypoxia. They had higher intracellular acetate, and secreted more H<sub>2</sub>O<sub>2</sub>, suggesting increased peroxisomal fatty acid β-oxidation. Simultaneously increased fatty acid synthesis and degradation would have \"wasted\" ATP in Hepa-1c4 cells, thus raising the [AMP]:[ATP] ratio, and further contributing to the upregulation of the AMPK pathway. Since these tumour cells can proliferate without the HIF-1/2 pathways, combinations of HIF1/2 inhibitors with PGC-1α or AMPK inhibitors should be explored."],"journal":["Cells"],"pubmed_title":["Survival Pathways of HIF-Deficient Tumour Cells: TCA Inhibition, Peroxisomal Fatty Acid Oxidation Activation and an AMPK-PGC-1α Hypoxia Sensor."],"pmcid":["PMC9688062"],"funding_grant_id":["C9545/A17197","C14303/A17197","C9545/A29580"],"pubmed_authors":["Basetti M","Stubbs M","Griffiths JR","Harris AL","McIntyre DJO","Boros LG","Golinska MA"],"additional_accession":[]},"is_claimable":false,"name":"Survival Pathways of HIF-Deficient Tumour Cells: TCA Inhibition, Peroxisomal Fatty Acid Oxidation Activation and an AMPK-PGC-1α Hypoxia Sensor.","description":"The HIF-1 and HIF-2 (HIF1/2) hypoxia responses are frequently upregulated in cancers, and HIF1/2 inhibitors are being developed as anticancer drugs. How could cancers resist anti-HIF1/2 therapy? We studied metabolic and molecular adaptations of HIF-1β-deficient Hepa-1c4, a hepatoma model lacking HIF1/2 signalling, which mimics a cancer treated by a totally effective anti-HIF1/2 agent. [1,2-<sup>13</sup>C<sub>2</sub>]-D-glucose metabolism was measured by SiDMAP metabolic profiling, gene expression by TaqMan, and metabolite concentrations by <sup>1</sup>H MRS. HIF-1β-deficient Hepa-1c4 responded to hypoxia by increasing glucose uptake and lactate production. They showed higher glutamate, pyruvate dehydrogenase, citrate shuttle, and malonyl-CoA fluxes than normal Hepa-1 cells, whereas pyruvate carboxylase, TCA, and anaplerotic fluxes decreased. Hypoxic HIF-1β-deficient Hepa-1c4 cells increased expression of PGC-1α, phospho-p38 MAPK, and PPARα, suggesting AMPK pathway activation to survive hypoxia. They had higher intracellular acetate, and secreted more H<sub>2</sub>O<sub>2</sub>, suggesting increased peroxisomal fatty acid β-oxidation. Simultaneously increased fatty acid synthesis and degradation would have \"wasted\" ATP in Hepa-1c4 cells, thus raising the [AMP]:[ATP] ratio, and further contributing to the upregulation of the AMPK pathway. Since these tumour cells can proliferate without the HIF-1/2 pathways, combinations of HIF1/2 inhibitors with PGC-1α or AMPK inhibitors should be explored.","dates":{"release":"2022-01-01T00:00:00Z","publication":"2022 Nov","modification":"2025-04-19T00:36:00.545Z","creation":"2025-04-07T11:40:35.972Z"},"accession":"S-EPMC9688062","cross_references":{"pubmed":["36429023"],"doi":["10.3390/cells11223595"]}}