Lack of a Functional VHL Gene Product Sensitizes Renal Cell Carcinoma Cells to the Apoptotic Effects of the Protein Synthesis Inhibitor Verrucarin A

• Published in: Neoplasia (New York, N.Y.) Vol. 14; no. 8; pp. 771 - IN28
• Main Authors: Woldemichael, Girma M, Turbyville, Thomas J, Vasselli, James R, Linehan, W. Marston, McMahon, James B
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.08.2012; Elsevier
• Subjects: Antineoplastic Agents, Phytogenic - pharmacology; Apoptosis - drug effects; Apoptosis - genetics; Carcinoma, Renal Cell - genetics; Carcinoma, Renal Cell - metabolism; Carcinoma, Renal Cell - pathology; Cell Line, Tumor; Cell Proliferation - drug effects; Humans; Kidney Neoplasms - genetics; Oncology; Peptide Chain Initiation, Translational - drug effects; Trichothecenes - pharmacology; Von Hippel-Lindau Tumor Suppressor Protein - genetics; Von Hippel-Lindau Tumor Suppressor Protein - metabolism; clear cell renal cell carcinoma; cFLIP; cellular-FLICE inhibitory protein; HTS; stress granule; VA; VHL-defective; cycloheximide; high-throughput screen; CHX; SG; von Hippel-Lindau; VHL-competent; VHL -; VHL gene protein product; VHL; verrucarin A or muconomycin A; CCRCC; pVHL; VHL-
• ISSN: 1476-5586; 1476-5586; 1522-8002
• DOI: 10.1593/neo.12852

Abstract Verrucarin A (VA) is a small molecule derived from the fungal plant pathogen Myrothecium verrucaria and was identified as a selective inhibitor of clear cell renal cell carcinoma (CCRCC) cell proliferation in a high-throughput screen of a library of naturally occurring small molecules. CCRCC arises as a result of loss-of-function mutations in the von Hippel-Lindau ( VHL ) gene. Here we show that VA inhibits protein translation initiation culminating in apoptosis through the extrinsic signaling pathway. Reintroduction of the VHL gene in CCRCC cells afforded resistance to VA's apoptotic effects. This resistance is mediated in part by the formation of stress granules that entrap signaling molecules that initiate the apoptotic signaling cascade. The VHL gene product was found to be a component of stress granules that develop as result of VA treatment. These findings reveal an important role for the VHL gene product in cytotoxic stress response and have important implications for the rational development of VA-related compounds in chemotherapeutic targeting of CCRCC.