Emetine promotes von Hippel-Lindau-independent degradation of hypoxia-inducible factor-2α in clear cell renal carcinoma.
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. Although several inhibitors of HIF-1α have been described, these drugs typically have a minimal affect on HIF-2α. 786-O is a VHL-deficient CCRCC cell line that constitutively expresses only HIF-2α and is therefore suitable for the 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 three additional VHL-renal cancer cell lines, was insensitive to the prolyl hydroxylase inhibitor dimethyloxaloyl glycine, and did not require neural precursor cell expressed developmentally down-regulated-8, suggesting that emetine accesses a previously undescribed cullin-independent proteasome degradation pathway for HIF-2α. These data support the use of emetine or structurally related compounds as useful leads for the identification of novel HIF-2α inhibitors.
Kong
Hye-Sik
HS
Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
Lee
Sunmin
S
Beebe
Kristin
K
Scroggins
Bradley
B
Gupta
Gopal
G
Lee
Min-Jung
MJ
Jung
Yun-Jin
YJ
Trepel
Jane
J
Neckers
Leonard
L
D051792:Basic Helix-Loop-Helix Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002292:Carcinoma, Renal Cell / Q000378:metabolism*; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000187:drug effects; D004640:Emetine / Q000494:pharmacology*; D006801:Humans; D007680:Kidney Neoplasms / Q000378:metabolism*; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000502:physiology*; D000099162:Endothelial PAS Domain-Containing Protein 1
D051792:Basic Helix-Loop-Helix Proteins; D004640:Emetine; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D000099162:Endothelial PAS Domain-Containing Protein 1
Cancer Res. 2005 Apr 15;65(8):3299-306
15833863
Oncogene. 2008 Sep 11;27(40):5354-8
18490920
Br J Cancer. 2007 Feb 12;96(3):403-7
17211469
Mol Pharmacol. 2006 Nov;70(5):1664-71
16880289
Am J Physiol Renal Physiol. 2004 Jul;287(1):F1-6
15180922
Int J Cancer. 2009 Feb 15;124(4):763-71
19030186
Cancer Res. 2001 Jul 1;61(13):5215-22
11431362
Neuro Oncol. 2005 Apr;7(2):134-53
15831232
Nat Rev Drug Discov. 2006 Aug;5(8):671-88
16883305
J Nat Prod. 2005 Jun;68(6):947-50
15974627
Mol Cell Biol. 2005 Jul;25(13):5675-86
15964822
Nat Rev Cancer. 2003 Oct;3(10):721-32
13130303
Fed Proc. 1973 Jun;32(6):1673-8
4575885
Cancer Cell. 2002 Apr;1(3):237-46
12086860
Nature. 1999 May 20;399(6733):271-5
10353251
Urol Oncol. 2009 May-Jun;27(3):238-45
19414111
Oncogene. 2000 Nov 16;19(48):5435-43
11114720
J Biol Chem. 2007 Jun 8;282(23):17032-40
17439941
Mol Pharmacol. 2004 Sep;66(3):612-9
15322253
Curr Opin Genet Dev. 2010 Feb;20(1):51-6
19942427
Mol Cell Biol. 2005 Apr;25(8):3163-72
15798202
Mol Cell Biol. 2003 Dec;23(24):9361-74
14645546
Cancer Cell. 2005 Aug;8(2):143-53
16098467
Cancer Res. 2005 Jun 1;65(11):4918-28
15930314
Cancer. 2009 May 15;115(10 Suppl):2262-72
19402056
J Biol Chem. 2002 Aug 16;277(33):29936-44
12052835
Cancer Cell. 2002 Apr;1(3):247-55
12086861
J Biol Chem. 2004 Apr 16;279(16):16128-35
14764593
Semin Cancer Biol. 2009 Feb;19(1):12-6
19114105
Nat Med. 2006 Jan;12(1):122-7
16341243
Cancer Res. 2006 Mar 1;66(5):2576-83
16510575
Oncogene. 2008 Feb 28;27(10):1404-11
17828303
Cell Cycle. 2007 Apr 15;6(8):919-26
17404509
Biochem J. 2003 Mar 15;370(Pt 3):1011-7
12479793
J Biol Chem. 2007 Mar 16;282(11):8019-26
17200123
Mol Biol Cell. 2006 Apr;17(4):1549-58
16421254
Cell Signal. 2005 Jan;17(1):1-9
15451019