Oligomycin inhibits HIF-1alpha expression in hypoxic tumor cells.

Abstract

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.

• Authors: Yanqing Gong, Faton H Agani
• Journal: American journal of physiology. Cell physiology (Am J Physiol Cell Physiol) Vol. 288 Issue 5 Pg. C1023-9 (May 2005) ISSN: 0363-6143 [Print] United States
• PMID: 15840558 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Amino Acids, Dicarboxylic
• Chromans
• DNA-Binding Proteins
• Enzyme Inhibitors
• HIF1A protein, human
• Hypoxia-Inducible Factor 1
• Hypoxia-Inducible Factor 1, alpha Subunit
• Nuclear Proteins
• Oligomycins
• Reactive Oxygen Species
• Transcription Factors
• Proton-Translocating ATPases
• Deferoxamine
• 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid
• oxalylglycine
• Acetylcysteine

Topics

• Acetylcysteine (pharmacology)
• Amino Acids, Dicarboxylic (toxicity)
• Cell Hypoxia (physiology)
• Chromans (pharmacology)
• DNA-Binding Proteins (metabolism)
• Deferoxamine (toxicity)
• Electron Transport (drug effects, physiology)
• Enzyme Inhibitors (pharmacology)
• Gene Expression Regulation, Neoplastic (drug effects, physiology)
• Humans
• Hypoxia-Inducible Factor 1
• Hypoxia-Inducible Factor 1, alpha Subunit
• Mitochondria (drug effects, metabolism)
• Nuclear Proteins (metabolism)
• Oligomycins (pharmacology)
• Proton-Translocating ATPases (antagonists & inhibitors, metabolism)
• Reactive Oxygen Species (metabolism)
• Transcription Factors (metabolism)
• Tumor Cells, Cultured