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

187 Scopus citations

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

Keywords

  • CELLCYCLE
  • CHEMBIO

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

Fingerprint Dive into the research topics of 'A Molecule Targeting VHL-Deficient Renal Cell Carcinoma that Induces Autophagy'. Together they form a unique fingerprint.

  • 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