6-gingerol induces cell cycle arrest and apoptosis through multiple mechanisms in human colorectal cancer cells

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6-gingerol, natural product of ginger, has been known to possess the anti-tumorigenic and pro-apoptotic activity although the mechanisms by which it prevents cancer growth are not well understood. Nonsteroidal anti-inflammatory drug activatedgene (NAG-1) is a novel gene associated with pro-apoptoticand anti-tumorigenic activities. In the present study, we examined whether 6-gingerol altered cyclin D1 and NAG-1 expression and determined cell growth in human colorectal cancer cells. 6-gingerol suppressed cell growth and induced G1 cell cycle arrest. 6-gingerol also inhibited cyclin D1 expression and induced NAG-1 expression. Transient transfection and promoter assay revealed that 6-gingerol inhibited β-catenin activity as well as cyclin D1 transactivation. In addition, 6-gingerol increased proteosomal degradation of cyclin D1. The induction of NAG-1 by 6-gingerol is mediated by GSK-3β pathway and PKC epsilon. The results suggest that 6-gingerol stimulates apoptosis through up-regulation of NAG-1 and G1 arrest through downregulation of cyclin D1.