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.

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.
Mesh Terms:
Antigens, CD95, Apoptosis, Caspase 2, Caspase 9, Caspases, Cell Line, Tumor, Cell Membrane Permeability, Cisplatin, DNA-Binding Proteins, Doxorubicin, Fluorouracil, Humans, Mitochondria, Mitochondrial Membranes, Mutagens, Nuclear Proteins, Phosphorylation, Protein Binding, Protein Kinase C-delta, Proto-Oncogene Proteins c-abl, RNA, Small Interfering, Reactive Oxygen Species, Tumor Suppressor Protein p53, Tumor Suppressor Proteins, bcl-X Protein
FEBS Lett.
Date: May. 15, 2006
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