Hypoxia in cancer cell metabolism and pH regulation

Abstract

At a molecular level, hypoxia induces the stabilization and activation of the alpha-subunit of an alpha/beta heterodimeric transcription factor, appropriately termed HIF (hypoxia-inducible factor). Hypoxia is encountered, in particular, in tumour tissues, as a result of an insufficient and defective vasculature present in a highly proliferative tumour mass. In this context the active HIF heterodimer binds to and induces a panel of genes that lead to modification in a vast range of cellular functions that allow cancer cells to not only survive but to continue to proliferate and metastasize. Therefore HIF plays a key role in tumorigenesis, tumour development and metastasis, and its expression in solid tumours is associated with a poor patient outcome. Among the many genes induced by HIF are genes responsible for glucose transport and glucose metabolism. The products of these genes allow cells to adapt to cycles of hypoxic stress by maintaining a level of ATP sufficient for survival and proliferation. Whereas normal cells metabolize glucose through a cytoplasmic- and mitochondrial-dependent pathway, cancer cells preferentially use a cytoplasmic, glycolytic pathway that leads to an increased acid load due, in part, to the high level of production of lactic acid. This metabolic predilection of cancer cells is primarily dependent directly on the HIF activity but also indirectly through changes in the activity of tumour suppressors and oncogenes. A better understanding of HIF-dependent metabolism and pH regulation in cancer cells should lead to further development of diagnostic tools and novel therapeutics that will bring benefit to cancer patients.