Journal
MOLECULAR CARCINOGENESIS
Volume 47, Issue 3, Pages 197-208Publisher
WILEY-LISS
DOI: 10.1002/mc.20374
Keywords
6-gingerol; NAG-1; cyclin D1; beta-catenin; PKC; GSK-3 beta
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Funding
- NCI NIH HHS [R21 CA109423-01A1, R21 CA109423, R21 CA109423-02] Funding Source: Medline
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6-Gingerol, a natural product of ginger, has been known to possess anti-tumorigenic and pro-apoptotic activities. However, the mechanisms by which it prevents cancer are not well understood in human colorectal cancer. Cyclin D1 is a proto-oncogene that is overexpressed in many cancers and plays a role in cell proliferation through activation by beta-catenin signaling. Nonsteroidal anti-inflammatory drug (NSAID)-activated gene-1 (NAG-1) is a cytokine associated with pro-apoptotic and anti-tumorigenic properties. In the present study, we examined whether 6-gingerol influences cyclin D1 and NAG-1 expression and determined the mechanisms by which 6-gingerol affects the growth of human colorectal cancer cells in vitro. 6-Gingerol treatment suppressed cell proliferation and induced apoptosis and G, cell cycle arrest. Subsequently, 6-gingerol suppressed cyclin D1 expression and induced NAG-1 expression. Cyclin D1 suppression was related to inhibition of P-catenin translocation and cyclin D1 proteolysis. Furthermore, experiments using inhibitors and siRNA transfection confirm the involvement of the PKC epsilon and glycogen synthase kinase (GSK)-3 beta pathways in 6-gingerol-induced NAG-1 expression. The results suggest that 6-gingerol stimulates apoptosis through upregulation of NAG-1 and G, cell cycle arrest through downregulation of cyclin D1. Multiple mechanisms appear to be involved in 6-gingerol action, including protein degradation as well as beta-catenin, PKC epsilon, and GSK-3 beta pathways. (C) 2007 Wiley-Liss, Inc.
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