Protein kinase C delta is not activated by caspase-3 and its inhibition is sufficient to induce apoptosis in the colon cancer line, COLO 205.
Activation of protein kinase C delta (PKCdelta) is believed to be pro-apoptotic. PKCdelta is reported to be reduced in colon cancers. Using a colon cancer cell line, COLO 205, we have examined the roles of PKCdelta in apoptosis and of caspase-3 in the activation and inhibition of PKCdelta. PKCdelta activation with bistratene A and its inhibition with rottlerin induced apoptosis. Effects of PKC activators and inhibitors were additive, suggesting that PKCdelta down-regulation was responsible for the effects on apoptosis. Different apoptotic pathways induced PKCdelta cleavage, but the fragment produced was inactive in kinase assays. Caspase-3 inhibition did not block DNA fragmentation or PKCdelta proteolysis despite blocking intracellular caspase-3 activity. Calpain inhibition with calpeptin did not prevent TPA-induced PKCdelta cleavage. We conclude that in colonocytes, inhibition of PKCdelta is sufficient to lead to caspase-3-independent apoptosis. Caspase-3 does not cleave PKCdelta to an active form, nor does caspase-3 inhibition block apoptosis.
Lewis
Aurélia E
AE
Division of Medical Sciences, The Medical School, University of Birmingham, B15 2TT, UK.
Susarla
Radhika
R
Wong
Benjamin C Y
BC
Langman
Michael J S
MJ
Eggo
Margaret C
MC
D000081:Acetamides / Q000494:pharmacology; D000098:Acetophenones / Q000494:pharmacology; D000470:Alkaloids; D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D053119:Benzophenanthridines; D001578:Benzopyrans / Q000494:pharmacology; D002154:Calpain / Q000037:antagonists & inhibitors; D053148:Caspase 3; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism / Q000502:physiology*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000737:chemistry / Q000378:metabolism / Q000473:pathology; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D053938:DNA Fragmentation / Q000187:drug effects; D004151:Dipeptides / Q000494:pharmacology; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005434:Flow Cytometry; D006657:Histones / Q000378:metabolism; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology; D007700:Kinetics; D010617:Phenanthridines / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D011493:Protein Kinase C / Q000378:metabolism / Q000502:physiology*; D051745:Protein Kinase C-delta; D011714:Pyrans / Q000494:pharmacology; D013141:Spiro Compounds / Q000494:pharmacology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D000081:Acetamides; D000098:Acetophenones; D000470:Alkaloids; D000590:Amino Acid Chloromethyl Ketones; D000970:Antineoplastic Agents; D053119:Benzophenanthridines; D001578:Benzopyrans; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D004151:Dipeptides; D004791:Enzyme Inhibitors; D006657:Histones; D010617:Phenanthridines; D011714:Pyrans; D013141:Spiro Compounds; D014409:Tumor Necrosis Factor-alpha; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; C059975:bistratene A; C071482:calpeptin; C085746:rottlerin; C016299:chelerythrine; C497258:PRKCD protein, human; D011493:Protein Kinase C; D051745:Protein Kinase C-delta; C505407:CASP3 protein, human; D002154:Calpain; D053148:Caspase 3; D020169:Caspases; D013755:Tetradecanoylphorbol Acetate; D007213:Indomethacin