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Carcinogenesis Advance Access published online on May 29, 2008
Carcinogenesis, doi:10.1093/carcin/bgn125
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

HIF and reactive oxygen species regulate oxidative phosphorylation in cancer

Eric Hervouet1,#,a, Alena Cízková2,3,#, Jocelyne Demont1, Alena Vojtísková2, Petr Pecina2, Nicole L.W. Franssen - van Hal5, Jaap Keijer5, Hélène Simonnet1,b, Robert Ivánek3,4, Stanislav Kmoch3, Catherine Godinotand1,* and Josef Houstek2

1 Centre de Génétique Moléculaire et Cellulaire, UMR 5534, Centre National de la Recherche Scientifique –Claude Bernard University of Lyon 1 –Villeurbanne, France
2 Institute of Physiology, Academy of Sciences of the Czech Republic, Videnska 1083, 142 20 Praha, Czech Republic
3 Institute of Inherited Metabolic Disorders, Faculty of Medicine, Charles University, Ke Karlovu 2, Prague, Czech Republic
4 Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, Videnska 1083, 142 20 Praha, Czech Republic
5 RIKILT - Institute of Food Safety, Wageningen, The Netherlands

* Corresponding author: Dr. C. Godinot ; Centre de Génétique Moléculaire et Cellulaire, UMR 5534, Centre National de la Recherche Scientifique – Université Claude Bernard de Lyon 1 – 43 Bvd du onze novembre, 69622 Villeurbanne, cedex, France. Telephone: +33-478364192 ; e-mail: godinot1{at}yahoo.com

A decrease in oxidative phosphorylation (OXPHOS) is characteristic of many cancer types and, in particular, of clear cell renal carcinoma (CCRC) deficient in vhl (von Hippel Lindau gene). In the absence of functional pVHL, HIF1-{alpha} and HIF2-{alpha} subunits are stabilized, which induces the transcription of many genes including those involved in glycolysis and ROS metabolism. Transfection of these cells with vhl is known to restore HIF-{alpha} subunit degradation and to reduce glycolytic genes transcription. We show that such transfection with vhl of 786-0 CCRC (which are devoid of HIF1-{alpha}), also increased the content of respiratory chain subunits. However, the levels of most transcripts encoding OXPHOS subunits were not modified. Inhibition of HIF2-{alpha} 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-{alpha} subunit by CoCl2 decreased respiratory chain subunit levels in CCRC cells expressing pVHL. In addition, HIF stimulated ROS production and mitochondrial Mn-SOD content. OXPHOS subunit content was also decreased by added H2O2. Interestingly, desferrioxamine that also stabilized HIF did not decrease respiratory chain subunit level. While CoCl2 significantly stimulates ROS production, desferrioxamine 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.

Key Words: Clear cell renal carcinoma • mitochondrial biogenesis • reactive oxygen species • Hypoxia-inducible factor • siRNA • microarrays • desferrioxamine • cobalt chloride • hydrogen peroxide • Mn-superoxide dismutase

# Eric HERVOUET and Alena CÍZKOVÁ contributed equally to this study.

a Present address : Inserm U601, Institute of biology, 9 quai Moncousu, F-44035 Nantes, France.

b Present address : UMR 5201, CNRS, Université Claude Bernard Lyon 1, F-69373 Lyon, France.

Received December 29, 2007; revised April 26, 2008; accepted May 14, 2008.


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