Role of caspase activation in butyrate-induced terminal differentiation of HT29 colon carcinoma cells.
Colon epithelial cells have a defined life span and undergo terminal differentiation as they mature and migrate to the luminal surface. The differentiation process can be induced in cultured colon cancer cells by sodium butyrate, which induces expression of various differentiation markers followed subsequently by cell death. In the present study, HT29 colorectal carcinoma cells were shown to undergo butyrate-induced caspase activation that was mainly produced through a mitochondrial pathway. Inhibition of caspase activation, either by peptide pan caspase inhibitor Z-VAD-FMK, by caspase 9 inhibitor Z-LEHD-FMK, or by overexpression of Bcl-XL, also inhibited the expression of differentiation markers. These findings suggest (a) that terminal differentiation of HT29 colon carcinoma cells is tightly linked to caspase activation and (b) that increased expression of anti-apoptotic members of the Bcl-2 family of proteins, as well as other inhibitors of caspase activation, has the potential to inhibit terminal differentiation and thereby may contribute to the progression of colon cancer.
Cai
Jiyang
J
The Department of Biochemistry, Emory University School of Medicine, 4157 Rollins Research Center, 1510 Clifton Road, Atlanta, GA 30322, USA. Jiyang.cai@vanderbilt.edu
Chen
Yan
Y
Murphy
T J
TJ
Jones
Dean P
DP
Sartorelli
Alan C
AC
D000230:Adenocarcinoma; D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002087:Butyrates / Q000494:pharmacology*; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism*; D045744:Cell Line, Tumor / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D003110:Colonic Neoplasms / Q000378:metabolism* / Q000473:pathology; D004789:Enzyme Activation; D006801:Humans; D009842:Oligopeptides / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D051020:bcl-X Protein
D000590:Amino Acid Chloromethyl Ketones; C494811:BCL2L1 protein, human; D002087:Butyrates; D061945:Caspase Inhibitors; D009842:Oligopeptides; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein; C403754:benzyloxycarbonyl-leucyl-glutamyl-histidyl-aspartic acid fluoromethyl ketone; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D020169:Caspases