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United States Department of Agriculture

Agricultural Research Service

Title: Molecular Mechanisms of (-)-Gossypol-Induced Apoptosis in Human Prostate Cancer Cells

Authors
item Huang, Yw - OHIO STATE UNIVERSITY
item Wang, Ls - OHIO STATE UNIVERSITY
item Chang, Hl - OHIO STATE UNIVERSITY
item Ye, W - OHIO STATE UNIVERSITY
item Dowd, Michael
item Wan, Peter
item Lin, Yc - OHIO STATE UNIVERSITY

Submitted to: Anticancer Research
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: March 27, 2006
Publication Date: March 28, 2006
Citation: Huang, Y., Wang, L., Chang, H., Ye, W., Dowd, M.K., Wan, P.J., Lin, Y. 2006. Molecular mechanisms of (-)-gossypol-induced apoptosis in human prostate cancer cells. Anticancer Research. 26:1925-1933.

Interpretive Summary: Gossypol, a natural compound present in cottonseeds and other parts of the cotton plant, possesses antiproliferative and proapoptotic effects in various cancer cells. Naturally, gossypol is a mixture of right-handed (+) and left-handed (-) optical isomers. The left-handed isomer, (-)-gossypol, is a more potent inhibitor of cancer cell growth. Here, we studied the molecular mechanisms of cell viability inhibition and apoptosis induced by (-)-gossypol in human prostate cancer cells. (-)-Gossypol treatment resulted in growth suppression in both primary cultured human prostate cancer epithelial cells and the prostate cancer cell line, DU-145. Inhibition of cancer cell growth was associated with both down-regulation and up-regulation of some specific molecules and proteins levels. Treatment of cells with 5-10 uM (-)-gossypol significantly enhanced apoptosis measured by DNA fragmentation. Moreover, (-)-gossypol activated caspases-3, -8, and -9 and increased PARP (poly (ADP-ribose) polymerase) cleavage. Furthermore, (-)-gossypol-induced apoptosis might be due to an increase of CAD (caspase-activated deoxyribonuclease) proteins and a decrease of ICAD (inhibitor of CAD) proteins. To further investigate the apoptotic pathways induced by (-)-gossypol, different caspase inhibitors were used to block caspase activities. The data demonstrated that (-)-gossypol resulted in apoptosis via the caspase-dependent pathways. These observations indicate that the apoptotic processes caused by (-)-gossypol in mediated by the regulation of the Bcl-2 and caspase families in human prostate cancer cells. Our data suggest that (-)-gossypol will have chemopreventive benefits in prostate cancer patients as well as in healthy individuals.

Technical Abstract: Gossypol, a natural compound present in cottonseeds, possesses antiproliferative and proapoptotic effects in various cancer cells. The (-)-gossypol enantiomer is a more potent inhibitor of cancer cell growth. Here, we studied the molecular mechanisms of cell viability inhibition and apoptosis induced by (-)-gossypol in human prostate cancer cells. (-)-Gossypol treatment resulted in growth suppression in both primary cultured human prostate cancer epithelial cells and the prostate cancer cell line, DU-145. Inhibition of cancer cell growth was associated with down-regulation of cyclin-D1, Rb, CDK4 and CDK6, and with up-regulation of p21 and TGF-beta1 mRNA and proteins levels, as determined by RT-PCR and Western Blot analyses, respectively. Treatment of cells with 5-10 uM (-)-gossypol significantly enhanced apoptosis measured by DNA fragmentation. We determined that the apoptotic mechanisms might be correlated with down-regulation of Bcl-2 and Bcl-xL and with up-regulation of Bax. Moreover, (-)-gossypol activated caspases-3, -8, and -9 and increased PARP (poly (ADP-ribose) polymerase) cleavage. Furthermore, (-)-gossypol-induced apoptosis might be due to an increase of CAD (caspase-activated deoxyribonuclease) proteins and a decrease of ICAD (inhibitor of CAD) proteins. To further investigate the apoptotic pathways induced by (-)-gossypol, different caspase inhibitors were used to block caspase activities. The data demonstrated that (-)-gossypol resulted in apoptosis via the caspase-dependent pathways. These observations indicate that the apoptotic processes caused by (-)-gossypol in mediated by the regulation of the Bcl-2 and caspase families in human prostate cancer cells. Our data suggest that (-)-gossypol will have chemopreventive benefits in prostate cancer patients as well as in healthy individuals.

Last Modified: 11/23/2014
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