PT  - JOURNAL ARTICLE
AU  - Hye-Sik Kong
AU  - Sunmin Lee
AU  - Kristin Beebe
AU  - Bradley Scroggins
AU  - Gopal Gupta
AU  - Min-Jung Lee
AU  - Yun-Jin Jung
AU  - Jane Trepel
AU  - Len Neckers
TI  - Emetine promotes VHL-independent degradation of hypoxia inducible factor-2α in clear cell renal carcinoma
AID  - 10.1124/mol.110.066514
DP  - 2010 Jan 01
TA  - Molecular Pharmacology
PG  - mol.110.066514
4099  - http://molpharm.aspetjournals.org/content/early/2010/09/02/mol.110.066514.short
4100  - http://molpharm.aspetjournals.org/content/early/2010/09/02/mol.110.066514.full
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.