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Molecular Pharmacology

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Research ArticleArticle

Emetine Promotes von Hippel-Lindau-Independent Degradation of Hypoxia-Inducible Factor-2α in Clear Cell Renal Carcinoma

Hye-Sik Kong, Sunmin Lee, Kristin Beebe, Bradley Scroggins, Gopal Gupta, Min-Jung Lee, Yun-Jin Jung, Jane Trepel and Leonard Neckers
Molecular Pharmacology December 2010, 78 (6) 1072-1078; DOI: https://doi.org/10.1124/mol.110.066514
Hye-Sik Kong
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Sunmin Lee
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Kristin Beebe
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Bradley Scroggins
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Gopal Gupta
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Min-Jung Lee
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Yun-Jin Jung
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Jane Trepel
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Leonard Neckers
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Abstract

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.

Footnotes

  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

    doi:10.1124/mol.110.066514.

  • ABBREVIATIONS:

    VHL
    von Hippel-Lindau
    CCRCC
    clear cell renal cell carcinoma
    HIF
    hypoxia-inducible factor
    ARNT
    aryl hydrocarbon receptor nuclear translocator
    CREB
    cAMP-response element-binding protein
    VEGF
    vascular endothelial growth factor
    GLUT-1
    glucose transporter-1
    TGF-α
    transforming growth factor-α
    DMOG
    dimethyloxaloyl glycine
    NEDD8
    neural precursor cell expressed developmentally down-regulated-8
    ALLN
    N-acetyl-Leu-Leu-norleucinal
    ALLM
    N-acetyl-l-leucyl-l-leucyl-l-methioninal
    PCR
    polymerase chain reaction
    siRNA
    small interfering RNA
    RT-PCR
    reverse transcriptase-polymerase chain reaction
    ELISA
    enzyme-linked immunosorbent assay
    CHX
    cycloheximide
    PS-341
    bortezomib
    MG132
    N-benzoyloxycarbonyl (Z)-Leu-Leu-leucinal.

  • Received May 19, 2010.
  • Accepted September 2, 2010.
  • Copyright © 2010 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 78 (6)
Molecular Pharmacology
Vol. 78, Issue 6
1 Dec 2010
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Research ArticleArticle

Emetine Promotes von Hippel-Lindau-Independent Degradation of Hypoxia-Inducible Factor-2α in Clear Cell Renal Carcinoma

Hye-Sik Kong, Sunmin Lee, Kristin Beebe, Bradley Scroggins, Gopal Gupta, Min-Jung Lee, Yun-Jin Jung, Jane Trepel and Leonard Neckers
Molecular Pharmacology December 1, 2010, 78 (6) 1072-1078; DOI: https://doi.org/10.1124/mol.110.066514

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Research ArticleArticle

Emetine Promotes von Hippel-Lindau-Independent Degradation of Hypoxia-Inducible Factor-2α in Clear Cell Renal Carcinoma

Hye-Sik Kong, Sunmin Lee, Kristin Beebe, Bradley Scroggins, Gopal Gupta, Min-Jung Lee, Yun-Jin Jung, Jane Trepel and Leonard Neckers
Molecular Pharmacology December 1, 2010, 78 (6) 1072-1078; DOI: https://doi.org/10.1124/mol.110.066514
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