title: Suppression of hypoxia-inducible factor 2alpha restores p53 activity via Hdm2 and reverses chemoresistance of renal carcinoma cells.
abstract: p53 mutations are rarely detected in clear cell renal cell carcinoma (CCRCC), but, paradoxically, these tumors remain highly resistant to chemotherapy and death receptor-induced death. Here, we show that the accumulation of hypoxia-inducible factor 2alpha (HIF2alpha), a critical oncogenic event in CCRCC following the loss of von Hippel-Lindau (VHL) tumor suppressor protein, leads to Hdm2-mediated suppression of p53. Primary CCRCC specimens exhibiting strong hypoxic signatures show increased levels of activated nuclear phospho-Hdm2(Ser(166)), which is concomitant with low p53 expression. The abrogation of Hdm2-p53 interaction using the small-molecule Hdm2 inhibitor nutlin-3 or the downregulation of HIF2alpha via HIF2alpha-specific short hairpin RNA or wild-type VHL reconstitution restores p53 function and reverses the resistance of CCRCC cells to Fas-mediated and chemotherapy-induced cell death. These findings unveil a mechanistic link between HIF2alpha and p53 and provide a rationale for combining Hdm2 antagonists with chemotherapy for the treatment of CCRCC.
authors.affiliation: Department of Laboratory Medicine, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Roberts
authors.forename: Ian R
authors.initials: IR
authors.lastname: Watson
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Evans
authors.forename: David A
authors.initials: DA
authors.lastname: Foster
authors.forename: Meredith S
authors.initials: MS
authors.lastname: Irwin
authors.forename: Michael
authors.initials: M
authors.lastname: Ohh
mesh_terms: D000906:Antibodies / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2 / Q000096:biosynthesis / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000378:metabolism*; D019014:fas Receptor / Q000502:physiology; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D000906:Antibodies; D051792:Basic Helix-Loop-Helix Proteins; D004317:Doxorubicin; D051057:Proto-Oncogene Proteins c-akt; D051736:Proto-Oncogene Proteins c-mdm2; D016159:Tumor Suppressor Protein p53; D019014:fas Receptor; D000099162:Endothelial PAS Domain-Containing Protein 1; C481004:CH-11 anti-fas antibody, human; C495901:TP53 protein, human; C497206:MDM2 protein, human