Tetrathiomolybdate inhibits mitochondrial complex IV and mediates degradation of hypoxia-inducible factor-1α in cancer cells.

Abstract

Hypoxia-inducible factor-1α (HIF-1α) is a transcription factor that triggers adaptive responses upon low oxygen conditions and plays a crucial role in cancer metabolism and therapy resistance. Tetrathiomolybdate (TM), a therapy option for copper overload disorder, has also been shown to be capable of limiting tumor angiogenesis, although its underlying mechanism remains unclear. Using ovarian and endometrial cancer cell lines, we observed that TM downregulates HIF-1α protein levels and HIF-transcriptional targets involved in tumor angiogenesis and glycolysis, but did not affect HIF-1α protein synthesis. TM-mediated HIF-1α downregulation was suppressed when HIF-prolyl hydroxylase activity was pharmacologically inhibited using deferoxamine or dimethyloxaloylglycine, and also when the oxygen-dependent degradation domains of HIF-1α, which are responsible for the interaction with HIF-prolyl hydroxylase, were deleted. These findings suggest that TM causes HIF-1α downregulation in a HIF-prolyl hydroxylase-dependent manner. Our studies showed that TM inhibits the activity of the copper-dependent mitochondrial complex IV and reduces mitochondrial respiration, thereby possibly increasing oxygen availability, which is crucial for HIF-prolyl hydroxylase activity. Pimonidazole staining also showed that TM elevates oxygen tension in hypoxic cells. Our studies provide mechanistic evidence for TM-mediated HIF-1α regulation and suggest its therapeutic potential as a method of blocking angiogenesis in ovarian and endometrial tumors.

• Authors: Kyu Kwang Kim, Sarah Abelman, Naohiro Yano, Jennifer R Ribeiro, Rakesh K Singh, Marla Tipping, Richard G Moore
• Journal: Scientific reports (Sci Rep) Vol. 5 Pg. 14296 (Oct 15 2015) ISSN: 2045-2322 [Electronic] England
• PMID: 26469226 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Hypoxia-Inducible Factor 1, alpha Subunit
• Molybdenum
• tetrathiomolybdate
• Electron Transport Complex IV
• Phosphatidylinositol 3-Kinases
• Proto-Oncogene Proteins c-akt
• Oxygen

Topics

• Cell Line, Tumor
• Cell Respiration (drug effects)
• Electron Transport Complex IV (antagonists & inhibitors, metabolism)
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit (metabolism)
• Molybdenum (pharmacology)
• Neoplasms (genetics, metabolism)
• Oxygen (metabolism)
• Phosphatidylinositol 3-Kinases (metabolism)
• Proteolysis (drug effects)
• Proto-Oncogene Proteins c-akt (metabolism)
• Signal Transduction (drug effects)