Multiple mechanisms are involved in 6-gingerol-induced cell growth arrest and apoptosis in human colorectal cancer cells

Mol Carcinog. 2008 Mar;47(3):197-208. doi: 10.1002/mc.20374.

Abstract

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.

MeSH terms

  • Anti-Inflammatory Agents, Non-Steroidal / metabolism
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects*
  • Caco-2 Cells
  • Catechols
  • Cell Line, Tumor
  • Cell Proliferation / drug effects*
  • Colorectal Neoplasms / drug therapy*
  • Colorectal Neoplasms / pathology
  • Cyclin D1 / metabolism
  • Dose-Response Relationship, Drug
  • Fatty Alcohols / pharmacology*
  • G1 Phase / drug effects
  • HT29 Cells
  • Humans
  • Luciferases / metabolism
  • Plasmids
  • S Phase / drug effects
  • Statistics as Topic
  • Transfection
  • beta Catenin / metabolism

Substances

  • Anti-Inflammatory Agents, Non-Steroidal
  • Antineoplastic Agents
  • Catechols
  • Fatty Alcohols
  • beta Catenin
  • Cyclin D1
  • gingerol
  • Luciferases