Oligomycin inhibits HIF-1alpha expression in hypoxic tumor cells.
Hypoxia-inducible factor-1 (HIF-1) is a key regulator of cellular responses to reduced oxygen availability. The contribution of mitochondria in regulation of HIF-1alpha in hypoxic cells has received recent attention. We demonstrate that inhibition of electron transport complexes I, III, and IV diminished hypoxic HIF-1alpha accumulation in different tumor cell lines. Hypoxia-induced HIF-1alpha accumulation was not prevented by the antioxidants Trolox and N-acetyl-cysteine. Oligomycin, inhibitor of F(0)F(1)-ATPase, prevented hypoxia-induced HIF-1alpha protein accumulation and had no effect on HIF-1alpha induction by hypoxia-mimicking agents desferrioxamine or dimethyloxalylglycine. The inhibitory effect of mitochondrial respiratory chain inhibitors and oligomycin on hypoxic HIF-1alpha content was pronounced in cells exposed to hypoxia (1.5% O(2)) but decreased markedly when cells were exposed to severe oxygen deprivation (anoxia). Taken together, these results do not support the role for mitochondrial reactive oxygen species in HIF-1alpha regulation, but rather suggest that inhibition of electron transport chain and impaired oxygen consumption affect HIF-1alpha accumulation in hypoxic cells indirectly via effects on prolyl hydroxylase function.
Gong
Yanqing
Y
Dept. of Anatomy, School of Medicine, Case Western Reserve Univ., 10900 Euclid Ave., Cleveland, OH 44106, USA. fxa5@po.cwru.edu
Agani
Faton H
FH
D000111:Acetylcysteine / Q000494:pharmacology; D000600:Amino Acids, Dicarboxylic / Q000633:toxicity; D015687:Cell Hypoxia / Q000502:physiology; D002839:Chromans / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000378:metabolism*; D003676:Deferoxamine / Q000633:toxicity; D004579:Electron Transport / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism*; D009840:Oligomycins / Q000494:pharmacology*; D006180:Proton-Translocating ATPases / Q000037:antagonists & inhibitors / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D000600:Amino Acids, Dicarboxylic; D002839:Chromans; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; C497442:HIF1A protein, human; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009687:Nuclear Proteins; D009840:Oligomycins; D017382:Reactive Oxygen Species; D014157:Transcription Factors; D006180:Proton-Translocating ATPases; D003676:Deferoxamine; C010643:6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid; C040947:oxalylglycine; D000111:Acetylcysteine