title: 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.affiliation: Molecular Therapeutics Laboratory, Program in Women's Oncology, Departments of Obstetrics and Gynecology, Women and Infants Hospital, Alpert Medical School of Brown University, Providence, RI, USA.
authors.forename: Kyu Kwang
authors.initials: KK
authors.lastname: Kim
authors.affiliation: Molecular Therapeutics Laboratory, Program in Women's Oncology, Departments of Obstetrics and Gynecology, Women and Infants Hospital, Alpert Medical School of Brown University, Providence, RI, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Abelman
authors.affiliation: Molecular Therapeutics Laboratory, Program in Women's Oncology, Departments of Obstetrics and Gynecology, Women and Infants Hospital, Alpert Medical School of Brown University, Providence, RI, USA.
authors.forename: Naohiro
authors.initials: N
authors.lastname: Yano
authors.affiliation: Molecular Therapeutics Laboratory, Program in Women's Oncology, Departments of Obstetrics and Gynecology, Women and Infants Hospital, Alpert Medical School of Brown University, Providence, RI, USA.
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Ribeiro
authors.affiliation: Molecular Therapeutics Laboratory, Program in Women's Oncology, Departments of Obstetrics and Gynecology, Women and Infants Hospital, Alpert Medical School of Brown University, Providence, RI, USA.
authors.forename: Rakesh K
authors.initials: RK
authors.lastname: Singh
authors.affiliation: Department of Biology, Providence College, Providence, RI, USA.
authors.forename: Marla
authors.initials: M
authors.lastname: Tipping
authors.affiliation: Molecular Therapeutics Laboratory, Program in Women's Oncology, Departments of Obstetrics and Gynecology, Women and Infants Hospital, Alpert Medical School of Brown University, Providence, RI, USA.
authors.forename: Richard G
authors.initials: RG
authors.lastname: Moore
mesh_terms: D045744:Cell Line, Tumor; D019069:Cell Respiration / Q000187:drug effects; D003576:Electron Transport Complex IV / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D008982:Molybdenum / Q000494:pharmacology*; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism*; D010100:Oxygen / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D059748:Proteolysis / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008982:Molybdenum; C020809:tetrathiomolybdate; D003576:Electron Transport Complex IV; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D010100:Oxygen