HIF-1 mediates the Warburg effect in clear cell renal carcinoma
Hypoxia-inducible factor 1 (HIF-1) is a transcription factor that functions as a master regulator of oxygen homeostasis in all metazoan species. O2-dependent hydroxylation of two proline residues in the HIF-1α subunit is necessary for the binding of the von Hippel–Lindau (VHL) protein, which is a component of a ubiquitin protein ligase that ubiquitinates HIF-1α, leading to its degradation by the proteasome. In the majority of cases of the clear cell type of renal carcinoma, both VHL genes are inactivated by mutation or epigenetic silencing, leading to dysregulated HIF-1 transcriptional activity. VHL loss-of-function leads, under aerobic conditions, to a HIF-1-dependent reprogramming of glucose and energy metabolism that includes increased glucose uptake, glycolysis, and lactate production accompanied by a reciprocal decrease in respiration. These findings delineate for the first time the molecular mechanisms underlying the Warburg effect in a human cancer.
KeywordsGlucose transport Glycolysis Hypoxia von Hippel–Lindau
Unable to display preview. Download preview PDF.
- Ivan M, Kondo K, Yang H, Kim W, Valiando J, Ohh M, Salic A, Asara JM, Lane WS, Kaelin WG Jr (2001) Science 292:464–468Google Scholar
- Iyer NV, Kotch LE, Agani F, Leung SW, Laughner E, Wenger RH, Gassmann M, Gearhart JD, Lawler AM, Yu AY, Semenza GL (1998) Genes Dev 12:149–162Google Scholar
- Jaakkola P, Mole DR, Tian YM, Wilson MI, Gielbert J, Gaskell SJ, Kriegsheim AV, Hebestreit HF, Mukherji M, Schofield CJ, Maxwell PH, Pugh CW, Ratcliffe PJ (2001) Science 292:468–472Google Scholar
- Jewell UR, Kvietikova I, Scheid A, Bauer C, Wenger RH, Gassmann M (2001) FASEB J 15:1312–1314Google Scholar
- Jiang B-H, Semenza GL, Bauer C, Marti HH (1996) Am J Physiol 271:C1172–C1180Google Scholar
- Lehninger AL (1982) Principles of biochemistry. Worth, New YorkGoogle Scholar
- Semenza GL, Roth PH, Fang H-M, Wang GL (1994) J Biol Chem 269:23757–23763Google Scholar
- Semenza GL, Wang GL (1992) Mol Cell Biol 12:5447–5454Google Scholar
- Steck TL, Kaufman S, Bader JP (1968) Cancer Res 28:1611–1619Google Scholar
- Wiesener MS, Turley H, Allen WE, Willam C, Eckardt KU, Talks KL, Wood SM, Gatter KC, Harris AL, Pugh CW, Ratcliffe PJ, Maxwell PH (1998) Blood 92:2260–2268Google Scholar
- Yu AY, Frid MG, Shimoda LA, Wiener CM, Stenmark K, Semenza GL (1998) Am J Physiol 275:L818–L826Google Scholar
- Zhang H, Gao P, Fukuda R, Kumar G, Krishnamachary B, Zeller KI, Dang CV, Semenza GL (2007) Cancer Cell 11:407–420Google Scholar