Abstract 3792: Phenethyl isothiocyanate inhibits oxidative phosphorylation to initiate reactive oxygen species-mediated death of human prostate cancer cells

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Abstract Phenethyl isothiocyanate (PEITC), a constituent of cruciferous vegetables (e.g., watercress), not only affords significant protection against chemically-induced cancer in experimental animals but also inhibits growth of human cancer cells in association with induction of apoptosis and autophagy. However, the mechanism by which PEITC causes cell death is not fully understood. Using LNCaP and PC-3 human prostate cancer cells as a model, we now demonstrate that the PEITC-induced cell death is initiated by reactive oxygen species (ROS) production due to inhibition of oxidative phosphorylation. Exposure of prostate cancer cells to pharmacologic concentrations of PEITC resulted in ROS production, which was accompanied by inhibition of complex-III activity, suppression of oxidative phosphorylation, and ATP depletion. These effects were not observed in a normal human prostate epithelial cell line (PrEC). The Rho-0 variants of LNCaP and PC-3 cells lacking normal oxidative phosphorylation were significantly more resistant to PEITC-mediated ROS generation, apoptotic DNA fragmentation, caspase-3 activation, and collapse of mitochondrial membrane potential compared with respective wild-type cells. The PEITC treatment resulted in activation of Bax in wild-type LNCaP and PC-3 cells, but not in their respective Rho-0 variants. Furthermore, Bax and Bak knockdown conferred significant protection against PEITC-induced apoptosis. The Rho-0 variants of LNCaP and PC-3 cells also resisted autophagy induction by PEITC treatment. In conclusion, the present study provides concrete experimental evidence to implicate ROS in initiation of PEITC-induced apoptosis and autophagy in human prostate cancer cells. This investigation was supported by the National Cancer Institute grant 2 RO1 CA101753-06. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3792.