A Molecule Targeting VHL-Deficient Renal Cell Carcinoma that Induces Autophagy

Sandra Turcotte, Denise A. Chan, Patrick D. Sutphin, Michael P. Hay, William A. Denny, Amato J. Giaccia

Research output: Contribution to journalArticle

177 Citations (Scopus)

Abstract

Renal cell carcinomas (RCCs) are refractory to standard therapies. The von Hippel-Lindau (VHL) tumor suppressor gene is inactivated in 75% of RCCs. By screening for small molecules selectively targeting VHL-deficient RCC cells, we identified STF-62247. STF-62247 induces cytotoxicity and reduces tumor growth of VHL-deficient RCC cells compared to genetically matched cells with wild-type VHL. STF-62247-stimulated toxicity occurs in a HIF-independent manner through autophagy. Reduction of protein levels of essential autophagy pathway components reduces sensitivity of VHL-deficient cells to STF-62247. Using a yeast deletion pool, we show that loss of proteins involved in Golgi trafficking increases killing by STF-62247. Thus, we have found a small molecule that selectively induces cell death in VHL-deficient cells, representing a paradigm shift for targeted therapy.

Original languageEnglish (US)
Pages (from-to)90-102
Number of pages13
JournalCancer Cell
Volume14
Issue number1
DOIs
StatePublished - Jul 8 2008

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Autophagy
Renal Cell Carcinoma
Tumor Suppressor Genes
Proteins
Cell Death
Yeasts
STF 62247
Therapeutics
Growth
Neoplasms

Keywords

  • CELLCYCLE
  • CHEMBIO

ASJC Scopus subject areas

  • Cancer Research
  • Cell Biology
  • Oncology

Cite this

Turcotte, S., Chan, D. A., Sutphin, P. D., Hay, M. P., Denny, W. A., & Giaccia, A. J. (2008). A Molecule Targeting VHL-Deficient Renal Cell Carcinoma that Induces Autophagy. Cancer Cell, 14(1), 90-102. https://doi.org/10.1016/j.ccr.2008.06.004

A Molecule Targeting VHL-Deficient Renal Cell Carcinoma that Induces Autophagy. / Turcotte, Sandra; Chan, Denise A.; Sutphin, Patrick D.; Hay, Michael P.; Denny, William A.; Giaccia, Amato J.

In: Cancer Cell, Vol. 14, No. 1, 08.07.2008, p. 90-102.

Research output: Contribution to journalArticle

Turcotte, S, Chan, DA, Sutphin, PD, Hay, MP, Denny, WA & Giaccia, AJ 2008, 'A Molecule Targeting VHL-Deficient Renal Cell Carcinoma that Induces Autophagy', Cancer Cell, vol. 14, no. 1, pp. 90-102. https://doi.org/10.1016/j.ccr.2008.06.004
Turcotte S, Chan DA, Sutphin PD, Hay MP, Denny WA, Giaccia AJ. A Molecule Targeting VHL-Deficient Renal Cell Carcinoma that Induces Autophagy. Cancer Cell. 2008 Jul 8;14(1):90-102. https://doi.org/10.1016/j.ccr.2008.06.004
Turcotte, Sandra ; Chan, Denise A. ; Sutphin, Patrick D. ; Hay, Michael P. ; Denny, William A. ; Giaccia, Amato J. / A Molecule Targeting VHL-Deficient Renal Cell Carcinoma that Induces Autophagy. In: Cancer Cell. 2008 ; Vol. 14, No. 1. pp. 90-102.
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