Multiple mechanisms are involved in 6-gingerol-induced cell growth arrest and apoptosis in human colorectal cancer cells.
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(1) cell cycle arrest. Subsequently, 6-gingerol suppressed cyclin D1 expression and induced NAG-1 expression. Cyclin D1 suppression was related to inhibition of beta-catenin translocation and cyclin D1 proteolysis. Furthermore, experiments using inhibitors and siRNA transfection confirm the involvement of the PKCepsilon and glycogen synthase kinase (GSK)-3beta pathways in 6-gingerol-induced NAG-1 expression. The results suggest that 6-gingerol stimulates apoptosis through upregulation of NAG-1 and G(1) 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, PKCepsilon, and GSK-3beta pathways.
The Laboratory of Environmental Carcinogenesis, Department of Pathobiology, College of Veterinary Medicine, University of Tennessee, Knoxville, Tennessee 37996-4542, USA.
Seong-Ho
SH
Lee
Maria
M
Cekanova
Seung Joon
SJ
Baek
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D018938:Caco-2 Cells; D002396:Catechols; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D019938:Cyclin D1 / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005233:Fatty Alcohols / Q000494:pharmacology*; D016193:G1 Phase / Q000187:drug effects; D019073:HT29 Cells; D006801:Humans; D008156:Luciferases / Q000378:metabolism; D010957:Plasmids; D000090063:Proto-Oncogene Mas; D016196:S Phase / Q000187:drug effects; D013223:Statistics as Topic; D014162:Transfection; D051176:beta Catenin / Q000378:metabolism
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000970:Antineoplastic Agents; D002396:Catechols; D005233:Fatty Alcohols; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D051176:beta Catenin; D019938:Cyclin D1; C007845:gingerol; D008156:Luciferases