Butyrate mediates Caco-2 cell apoptosis via up-regulation of pro-apoptotic BAK and inducing caspase-3 mediated cleavage of poly-(ADP-ribose) polymerase (PARP)

Cell Death Differ. 1999 Aug;6(8):729-35. doi: 10.1038/sj.cdd.4400545.


Butyrate exerts potent anti-tumor effects by inhibiting cancer cell growth and inducing apoptosis. However, the molecular mechanisms mediating these effects remain largely unknown. Using the Caco-2 cell line, a well established model of colon cancer cells, our data show that butyrate induced apoptosis (maximum 79%) is mediated via activation of the caspase-cascade. A key event was the proteolytic activation of caspase-3, triggering degradation of poly-(ADP-ribose) polymerase (PARP). Inactivation of caspase-3 with the tetrapeptide zDEVD-FMK completely inhibited the apoptotic response to butyrate. In parallel, butyrate potently up-regulated the expression of the pro-apoptotic protein bak, without changing Caco-2 cell bcl-2 expression. Butyrate-induced Caco-2 cell apoptosis was completely blocked by the addition of cycloheximide, indicating the necessity of protein synthesis. However, when this inhibitor was added at a time point where bak expression was already enhanced (12 - 16 h after butyrate stimulation), it failed to protect Caco-2 cells against apoptosis. Taken together, these data provide evidence that the molecular events involved in butyrate induced colon cancer cell apoptosis include the caspase-cascade and the mitochondrial bcl-pathway.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis* / drug effects
  • Butyrates / metabolism*
  • Butyrates / pharmacology
  • Caco-2 Cells
  • Caspase 3
  • Caspases / biosynthesis
  • Caspases / metabolism*
  • Cell Division
  • Cycloheximide / pharmacology
  • Cysteine Proteinase Inhibitors / pharmacology
  • Enzyme Activation
  • Enzyme Induction
  • Humans
  • Membrane Proteins / biosynthesis*
  • Oligopeptides / pharmacology
  • Poly(ADP-ribose) Polymerases / metabolism*
  • Protein Biosynthesis
  • Protein Synthesis Inhibitors / pharmacology
  • Proto-Oncogene Proteins c-bcl-2 / biosynthesis*
  • Up-Regulation*
  • bcl-2 Homologous Antagonist-Killer Protein


  • BAK1 protein, human
  • Butyrates
  • Cysteine Proteinase Inhibitors
  • Membrane Proteins
  • Oligopeptides
  • Protein Synthesis Inhibitors
  • Proto-Oncogene Proteins c-bcl-2
  • bcl-2 Homologous Antagonist-Killer Protein
  • benzoylcarbonyl-aspartyl-glutamyl-valyl-aspartyl-fluoromethyl ketone
  • Cycloheximide
  • Poly(ADP-ribose) Polymerases
  • CASP3 protein, human
  • Caspase 3
  • Caspases