Journal Article

HIF and reactive oxygen species regulate oxidative phosphorylation in cancer

Eric Hervouet, Alena Cízková, Jocelyne Demont, Alena Vojtísková, Petr Pecina, Nicole L.W. Franssen-van Hal, Jaap Keijer, Hélène Simonnet, Robert Ivánek, Stanislav Kmoch, Catherine Godinot and Josef Houstek

in Carcinogenesis

Volume 29, issue 8, pages 1528-1537
Published in print August 2008 | ISSN: 0143-3334
Published online May 2008 | e-ISSN: 1460-2180 | DOI:
HIF and reactive oxygen species regulate oxidative phosphorylation in cancer

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  • Clinical Cytogenetics and Molecular Genetics


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A decrease in oxidative phosphorylation (OXPHOS) is characteristic of many cancer types and, in particular, of clear cell renal carcinoma (CCRC) deficient in von Hippel–Lindau (vhl) gene. In the absence of functional pVHL, hypoxia-inducible factor (HIF) 1-α and HIF2-α subunits are stabilized, which induces the transcription of many genes including those involved in glycolysis and reactive oxygen species (ROS) metabolism. Transfection of these cells with vhl is known to restore HIF-α subunit degradation and to reduce glycolytic genes transcription. We show that such transfection with vhl of 786-0 CCRC (which are devoid of HIF1-α) also increased the content of respiratory chain subunits. However, the levels of most transcripts encoding OXPHOS subunits were not modified. Inhibition of HIF2-α synthesis by RNA interference in pVHL-deficient 786-0 CCRC also restored respiratory chain subunit content and clearly demonstrated a key role of HIF in OXPHOS regulation. In agreement with these observations, stabilization of HIF-α subunit by CoCl2 decreased respiratory chain subunit levels in CCRC cells expressing pVHL. In addition, HIF stimulated ROS production and mitochondrial manganese superoxide dismutase content. OXPHOS subunit content was also decreased by added H2O2. Interestingly, desferrioxamine (DFO) that also stabilized HIF did not decrease respiratory chain subunit level. While CoCl2 significantly stimulates ROS production, DFO is known to prevent hydroxyl radical production by inhibiting Fenton reactions. This indicates that the HIF-induced decrease in OXPHOS is at least in part mediated by hydroxyl radical production.

Journal Article.  7216 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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