A Molecule Targeting VHL-deficient Renal Cell Carcinoma That Induces Autophagy

Overview

Journal Cancer Cell

Publisher Cell Press

Specialty Oncology

Date 2008 Jul 5

PMID 18598947

Citations 126

Authors

Sandra Turcotte

Denise A Chan

Patrick D Sutphin

Michael P Hay

William A Denny

Amato J Giaccia

Affiliations

Soon will be listed here.

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.

Citing Articles

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