Protein kinase PKC delta and c-Abl are required for mitochondrial apoptosis induction by genotoxic stress in the absence of p53, p73 and Fas receptor |
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Authors: | Lasfer Malika Davenne Lise Vadrot Nathalie Alexia Catherine Sadji-Ouatas Zahia Bringuier Annie-France Feldmann Gérard Pessayre Dominique Reyl-Desmars Florence |
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Affiliation: | INSERM, U773, Equipe 5, Centre de Recherche Bichat Beaujon CRB3, BP416, F-75018 Paris, France. |
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Abstract: | Doxorubicin, cis-diamminedichloroplatinum (II) and 5-fluorouracil used in chemotherapy induce apoptosis in Hep3B cells in the absence of p53, p73, and functional Fas. Since mediators remain unknown, the requirement of PKC delta (PKCdelta) and c-Abl was investigated. Suppression of c-Abl or PKCdelta expression using SiRNAs impaired PARP cleavage, Gleevec and/or rottlerin inhibited the induction of the subG1 phase and the increase of reactive oxygen species level. Co-precipitations and phosphorylations to mitochondria of c-Abl, PKCdelta and Bcl-X(L/s) were induced. A depolarization of the mitochondrial membrane and activations of caspase-2 and -9 were observed. We propose that, in the absence of p53, p73 and Fas, genotoxic drugs could require both PKCdelta and c-Abl to induce apoptosis through the mitochondrial pathway. |
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Keywords: | DOX, doxorubicin cDDP, cis-diamminedichloroplatinum (II) 5-FU, 5-fluorouracil PKCδ, PKC delta MMP, mitochondrial membrane permeabilization cyt c, cytochrome c ROS, reactive oxygen species PI, propidium iodide DAPI, di-amidino-phenyl-indole tert-butyl, tert-butylhydroperoxide CCCP, carbonyl-cyanide-m-chloro-phenyl-hydrazone |
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