Involvement of protein kinase C-regulated ceramide generation in inostamycin-induced apoptosis.
Activation of caspases is commonly involved in the apoptosis induced by various anticancer drugs. However, the upstream events leading to the activation of caspases seem to be specific to each anticancer drug. In the present study, we examined the possible involvement of protein kinase C (PKC) and ceramide generation in caspase-3(-like) protease activation induced by inostamycin, a phosphatidylinositol synthesis inhibitor. Treatment of cells with 12-O-tetradecanoyl phorbol-13-acetate (TPA), an activator of PKC, suppressed the release of cytochrome c from mitochondria and the activation of caspase-3(-like) proteases in inostamycin-treated cells, but not in other anticancer drug-treated cells. Inostamycin induced the elevation of intracellular ceramide levels, and fumonisin B1, an inhibitor of ceramide synthase, inhibited inostamycin-induced cytochrome c release, caspase-3(-like) protease activation, and apoptosis. Moreover, TPA also inhibited inostamycin-induced ceramide synthesis. Taken together, our results suggest that inostamycin-induced apoptosis is mediated by PKC-regulated ceramide generation, leading to the activation of a caspase cascade.
Kawatani
M
M
Department of Applied Chemistry, Faculty of Science and Technology, Keio University, Yokohama, 223-8522, Japan.
Simizu
S
S
Osada
H
H
Takada
M
M
Arber
N
N
Imoto
M
M
D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002273:Carcinogens / Q000494:pharmacology; D018288:Carcinoma, Small Cell; D053148:Caspase 3; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002518:Ceramides / Q000096:biosynthesis*; D003574:Cytochrome c Group / Q000378:metabolism; D019852:Diacylglycerol Kinase / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D005663:Furans / Q000494:pharmacology; D006801:Humans; D008175:Lung Neoplasms; D008928:Mitochondria / Q000201:enzymology; D011493:Protein Kinase C / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000166:cytology / Q000201:enzymology
D000900:Anti-Bacterial Agents; D002273:Carcinogens; D061945:Caspase Inhibitors; D002518:Ceramides; D003574:Cytochrome c Group; D005663:Furans; D011506:Proteins; C071861:inostamycin; D019852:Diacylglycerol Kinase; D011493:Protein Kinase C; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D013755:Tetradecanoylphorbol Acetate