The hypoxia-inducible factor (HIF-1), in addition to genetic and epigenetic changes, is largely responsible for alterations in cell metabolism in hypoxic tumour cells. This transcription factor not only favours cell proliferation through the metabolic shift from oxidative phosphorylation to glycolysis and lactic acid production but also stimulates nutrient supply by mediating adaptive survival mechanisms. These include epithelial-mesenchymal transition, angiogenesis, autophagy, and synthesis and storage of lipid and glycogen. HIF-1 also ensures survival by correcting tumour acidosis via increased expression of the carbonic anhydrase CA IX and the lactate/H+ symporter MCT4. The targeting of key HIF-1-mediated steps, responsible for exacerbated glycolysis and pHi-control, and of the 'guardian of cellular energy' AMP-kinase should offer novel therapeutic opportunities to fight cancer.
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