RT Journal Article
SR Electronic
T1 Emetine promotes VHL-independent degradation of hypoxia inducible factor-2α in clear cell renal carcinoma
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP mol.110.066514
DO 10.1124/mol.110.066514
A1 Hye-Sik Kong
A1 Sunmin Lee
A1 Kristin Beebe
A1 Bradley Scroggins
A1 Gopal Gupta
A1 Min-Jung Lee
A1 Yun-Jin Jung
A1 Jane Trepel
A1 Len Neckers
YR 2010
UL http://molpharm.aspetjournals.org/content/early/2010/09/02/mol.110.066514.abstract
AB Inactivating mutations of the von Hippel-Lindau (VHL) tumor suppressor gene are associated with inherited VHL syndrome which is characterized by susceptibility to a variety of neoplasms including central nervous system hemangioblastoma and clear cell renal cell carcinoma (CCRCC). Mutations in the VHL gene are also found in the majority of sporadic clear cell renal carcinoma, the most common malignant neoplasm of the human kidney. Inactivation of VHL ubiquitin ligase is associated with normoxic stabilization of hypoxia-inducible factor-1α and 2-α (HIF-1α and HIF-2α), transcriptional regulators of tumor angiogenesis, invasion, survival, and glucose utilization. HIF-2α has been particularly implicated in the development of CCRCC. While several inhibitors of HIF-1α have been described, these drugs typically have minimal impact on HIF-2α. 786-O is a VHL-deficient CCRCC cell line that constitutively expresses only HIF-2α, and is therefore suitable for screening of novel HIF-2α, inhibitors. Using this cell line, we have identified emetine as a specific inhibitor of HIF-2α protein stability and transcriptional activity. Without altering HIF-2α mRNA level, emetine rapidly and dramatically down-regulated HIF-2α protein expression in 786-O cells. HIF-2α down-regulation was accompanied by HIF-2α ubiquitination, and was reversed by proteasome inhibition. Emetine-induced HIF-2α down-regulation was confirmed in 3 additional VHL- renal cancer cell lines, was insensitive to the prolyl hydroxylase inhibitor dimethyloxaloyl glycine, and did not require NEDD8, suggesting that emetine accesses a previously undescribed cullin-independent proteasome degradation pathway for HIF-2α. These data support utilization of emetine or structurally related compounds as useful leads for identification of novel HIF-2α inhibitors.