Redistribution of activated caspase-3 to the nucleus during butyric acid-induced apoptosis.
The colonic epithelial cells near the top of the crypt and in the lumen have been shown to undergo apoptosis. Since butyric acid is the major short-chain fatty acid produced by fermentation of dietary fiber in the large bowel, it has been proposed that it could act as an important regulator of apoptosis in colorectal cancer. Here we report that in cells treated with butyric acid, the cleavage of DNA-PKcs was paralleled or preceded by the induction of activation of caspase-3, and these events were inhibited by Bcl-2 overexpression. We also demonstrated the redistribution of activated caspase-3 to the nuclear compartment where it locally cleaves DNA-PKcs and poly(ADP-ribose) polymerase, and cleaved fragments were released in the cytosolic compartment. The observed activation of caspase-3 and nuclear cleavage of its substrates and their subsequent release into the cytosol were inhibited by a specific caspase-3 inhibitor, the tetrapeptide DEVD-CHO. These findings suggest that relocalization of activated caspase-3 to the nucleus may constitute an important apoptotic signal during butyric acid-induction of apoptosis human colorectal cancer cells.
Cell Growth Regulation Laboratory, University of Texas M.D. Anderson Cancer Center, Houston, Texas, 77030, USA.
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Mandal
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Adam
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Kumar
D017209:Apoptosis / Q000187:drug effects*; D020148:Butyric Acid / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D053148:Caspase 3; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism*; D020134:Catalytic Domain; D002467:Cell Nucleus / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000201:enzymology / Q000378:metabolism; D003513:Cycloheximide / Q000494:pharmacology; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D003600:Cytosol / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D051747:DNA-Activated Protein Kinase; D004268:DNA-Binding Proteins; D004789:Enzyme Activation / Q000187:drug effects; D004792:Enzyme Precursors / Q000378:metabolism; D006801:Humans; D018613:Microscopy, Confocal; D008970:Molecular Weight; D009687:Nuclear Proteins; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D013467:Sulindac / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D004268:DNA-Binding Proteins; D004792:Enzyme Precursors; D009687:Nuclear Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D020148:Butyric Acid; D013467:Sulindac; D003513:Cycloheximide; D011065:Poly(ADP-ribose) Polymerases; D051747:DNA-Activated Protein Kinase; C497263:PRKDC protein, human; D017346:Protein Serine-Threonine Kinases; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases