Butyric acid induces apoptosis by up-regulating Bax expression via stimulation of the c-jun N-terminal kinase/activation protein-1 pathway in human colon cancer cells

Background & Aims: The colonic epithelial cells near the top of the crypt h ave been shown to undergo apoptosis. Because butyric acid (BA) is the major short-chain fatty acid produced by fermentation of dietary fiber in the la rge bowel, it may be an important regulator of apoptosis in colorectal canc er. We investigated which signaling pathway is triggered by BA to undergo a poptosis in human colorectal cancer cells. Methods: Human DiFi and FET colo rectal cells were treated with BA to undergo apoptosis and were assayed for activation of c-Jun N-terminal kinase (JNK), transcription factor activati on protein 1 (AP1) and NF-kappaB, and the proapoptotic molecule Bax. The co ntribution of specific pathways was assessed by examining the effects of do minant-negative mutants of JNK/AP1 or NF-kappaB on BA-induced Bax expressio n and apoptosis. Results: BA-mediated DNA fragmentation and Bax induction w ere preceded by early stimulation of JNK, and the DNA-binding activities of AP1 and NF-kappaB. BA-induced enhancement of DNA fragmentation and stimula tion of Bax promoter activity were blocked by the expression of dominant-ne gative mutants of JNK1 or AP1 but not NF-kappaB. Conclusions: These finding s suggest that apoptosis triggered by BA involves transcriptional stimulati on of the Bax gene via activation of the JNK/AP1 pathway in colonic epithel ial cells.