Phosphatidylinositol 3-kinase and protein kinase C are required for the inhibition of caspase activity by epidermal growth factor.
The mechanism by which growth factors exert an anti-apoptotic function on many cell types is not well understood. This issue is addressed in relation to epidermal growth factor (EGF) which inhibits apoptosis induced by staurosporine or wortmannin in an epithelial tumour cell line (CNE-2). The presence of EGF substantially reduced the in vitro Ac-DEVD-AMC hydrolytic activity and almost completely suppressed the intracellular cleavage of poly(ADP-ribose) polymerase in staurosporine- or wortmannin-treated cells. Staurosporine but not wortmannin caused the intracellular proteolytic processing of pro-caspase-3 and this event was transiently inhibited by EGF. Staurosporine-induced apoptosis was not inhibited by EGF in the presence of wortmannin or LY294002. Similarly, EGF failed to inhibit wortmannin-induced apoptosis in the presence of staurosporine, chelerythrine chloride or Gö6850. These results suggest that phosphatidylinositol 3-kinase and protein kinase C play a role in the survival function of EGF but the reduction of cellular caspase activity cannot be satisfactorily explained by a lack of pro-caspase-3 activation.
Department of Biochemistry, Faculty of Medicine, University of Hong Kong, Hong Kong, PR China.
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D000470:Alkaloids; D000730:Androstadienes / Q000037:antagonists & inhibitors / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D053119:Benzophenanthridines; D015153:Blotting, Western; D053148:Caspase 3; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D002843:Chromatin / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D002867:Chromones / Q000494:pharmacology; D053938:DNA Fragmentation / Q000187:drug effects; D004792:Enzyme Precursors / Q000378:metabolism; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D005434:Flow Cytometry; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D008301:Maleimides / Q000494:pharmacology; D008970:Molecular Weight; D009025:Morpholines / Q000494:pharmacology; D010617:Phenanthridines / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019311:Staurosporine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D000077191:Wortmannin
D000470:Alkaloids; D000730:Androstadienes; D053119:Benzophenanthridines; D053148:Caspase 3; D061945:Caspase Inhibitors; D020169:Caspases; D002843:Chromatin; D002867:Chromones; D004792:Enzyme Precursors; D004815:Epidermal Growth Factor; D007211:Indoles; D008301:Maleimides; D009025:Morpholines; D010617:Phenanthridines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011065:Poly(ADP-ribose) Polymerases; D011493:Protein Kinase C; D019311:Staurosporine; D013755:Tetradecanoylphorbol Acetate; D000077191:Wortmannin; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C016299:chelerythrine; C505407:CASP3 protein, human; C070515:bisindolylmaleimide I