Abstract 3807: Gugulipid-induced apoptosis in human prostate cancer cells is regulated by Bax/Bak and Bcl-xL

Abstract

Abstract Indian Ayurvedic medicinal plant Commiphora mukul has been safely used for treatment of different disorders for thousands of years. Our previous studies have shown that the extract of Commiphora mukul, gugulipid (GL), inhibits growth of human prostate cancer (Pca) cells, but not a normal prostate epithelial cell line (PrEC), by causing apoptosis. We also showed that GL-mediated inhibition of Pca cell proliferation correlated with reactive oxygen species (ROS) production. The present study was designed to gain insight into the mechanism of GL-induced apoptosis downstream of ROS production. We found that the GL-induced apoptosis correlated with induction of proapoptotic proteins Bax and Bak and down-regulation of antiapoptotic proteins Bcl-2 and Bcl-xL in LNCaP and PC-3 cells. The SV40-immortalized mouse embryonic fibroblasts derived from Bax and Bak double knockout mice were significantly more resistant to GL-induced apoptotic cell death (DNA fragmentation and cleavage of PARP) compared with wild-type mouse embryonic fibroblasts. Bcl-xL overexpression in PC-3 cells conferred protection against GL-induced apoptotic cell death. The GL treatment caused activation of c-Jun-N-terminal kinase (JNK), which functions upstream of Bax activation in apoptotic response to various stimuli. Pharmacological inhibition of JNK conferred partial yet significant protection against GL-induced apoptosis. The GL-mediated apoptosis and conformational change of Bax was markedly suppressed by ectopic expression of catalytically inactive mutant of JNK kinase JNKK2 (AA) in LNCaP cells. In conclusion, the present study indicates that Bax/Bak and Bcl-xL regulate GL-induced apoptosis in human prostate cancer cells. This investigation was supported by USPHS grant R21 CA143104-01. 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 3807.