165 © The Authors Journal compilation © 2007 Biochemical Society 12 Hypoxia in cancer cell metabolism and pH regulation M. Christiane Brahimi-Horn 1 and Jacques Pouysségur Institute of Signaling, Developmental Biology and Cancer Research, CNRS UMR 6543, University of Nice, Centre A. Lacassagne, 33 Avenue Valombrose, 06189 Nice, France Abstract At a molecular level, hypoxia induces the stabilization and activation of the - subunit of an / heterodimeric transcription factor, appropriately termed HIF (hypoxia-inducible factor). Hypoxia is encountered, in particular, in tumour tissues, as a result of an insuffcient 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 modifcation in a vast range of cellular functions that allow cancer cells to not only survive but to continue to prolifer- ate 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 suffcient for survival and proliferation. Whereas normal cells metabo- lize 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. 1 To whom correspondence should be addressed (email brahimi@unice.fr). POIN003_C12[165-178].indd 165 POIN003_C12[165-178].indd 165 7/12/07 7:38:22 PM 7/12/07 7:38:22 PM