HIF and reactive oxygen species regulate oxidative phosphorylation in cancer.
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-alpha and HIF2-alpha 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-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 CoCl(2) 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 H(2)O(2.) Interestingly, desferrioxamine (DFO) that also stabilized HIF did not decrease respiratory chain subunit level. While CoCl(2) 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.
Hervouet
Eric
E
Centre de Génétique Moléculaire et Cellulaire, UMR 5534, Centre National de la Recherche Scientifique, Claude Bernard University of Lyon 1, 43 Boulevard du onze novembre, 69622 Villeurbanne, Cedex, France.
Cízková
Alena
A
Demont
Jocelyne
J
Vojtísková
Alena
A
Pecina
Petr
P
Franssen-van Hal
Nicole L W
NL
Keijer
Jaap
J
Simonnet
Hélène
H
Ivánek
Robert
R
Kmoch
Stanislav
S
Godinot
Catherine
C
Houstek
Josef
J
D051784:Aryl Hydrocarbon Receptor Nuclear Translocator / Q000235:genetics* / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D003035:Cobalt / Q000494:pharmacology; D003598:Cytoskeletal Proteins; D003676:Deferoxamine / Q000494:pharmacology; D006019:Glycolysis / Q000235:genetics; D006706:Homeostasis; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics* / Q000378:metabolism*; D018832:Molecular Chaperones; D009369:Neoplasms / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D010085:Oxidative Phosphorylation; D017382:Reactive Oxygen Species / Q000378:metabolism*; D016897:Respiratory Burst / Q000187:drug effects / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction
C497396:ARNT protein, human; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D018832:Molecular Chaperones; D017382:Reactive Oxygen Species; C108825:VBP1 protein, human; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D003035:Cobalt; D006861:Hydrogen Peroxide; C018021:cobaltous chloride; D003676:Deferoxamine