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 (PKC6) and c-Abl was investigated. Suppression of c-Abl or PKC6 expression using SiRNAs impaired PARP cleavage, Gleevec (R) 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, PKC6 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 PKC6 and c-Abl to induce apoptosis through the mitochondrial pathway. (c) 2006 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.