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

Gastroenterology. 2001 Jan;120(1):71-8. doi: 10.1053/gast.2001.20897.


Background & aims: The colonic epithelial cells near the top of the crypt have been shown to undergo apoptosis. Because butyric acid (BA) is the major short-chain fatty acid produced by fermentation of dietary fiber in the large bowel, it may be an important regulator of apoptosis in colorectal cancer. We investigated which signaling pathway is triggered by BA to undergo apoptosis in human colorectal cancer cells.

Methods: Human DiFi and FET colorectal cells were treated with BA to undergo apoptosis and were assayed for activation of c-Jun N-terminal kinase (JNK), transcription factor activation protein 1 (AP1) and NF-kappaB, and the proapoptotic molecule Bax. The contribution of specific pathways was assessed by examining the effects of dominant-negative mutants of JNK/AP1 or NF-kappaB on BA-induced Bax expression and apoptosis.

Results: BA-mediated DNA fragmentation and Bax induction were preceded by early stimulation of JNK, and the DNA-binding activities of AP1 and NF-kappaB. BA-induced enhancement of DNA fragmentation and stimulation of Bax promoter activity were blocked by the expression of dominant-negative mutants of JNK1 or AP1 but not NF-kappaB.

Conclusions: These findings suggest that apoptosis triggered by BA involves transcriptional stimulation of the Bax gene via activation of the JNK/AP1 pathway in colonic epithelial cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects*
  • Apoptosis / physiology
  • Butyric Acid / pharmacology*
  • Colorectal Neoplasms*
  • DNA Fragmentation / drug effects
  • Gene Expression Regulation / drug effects
  • Histamine Antagonists / pharmacology*
  • Humans
  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinases / metabolism*
  • Mutagenesis / physiology
  • Promoter Regions, Genetic / physiology
  • Proto-Oncogene Proteins / genetics*
  • Proto-Oncogene Proteins c-bcl-2*
  • Transcription Factor AP-1 / metabolism*
  • Transcriptional Activation / physiology
  • Tumor Cells, Cultured / cytology
  • Tumor Cells, Cultured / drug effects
  • Tumor Cells, Cultured / physiology
  • bcl-2-Associated X Protein


  • BAX protein, human
  • Histamine Antagonists
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • Transcription Factor AP-1
  • bcl-2-Associated X Protein
  • Butyric Acid
  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinases