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.
Lasfer
Malika
M
INSERM, U773, Equipe 5, Centre de Recherche Bichat Beaujon CRB3, BP416, F-75018 Paris, France.
Davenne
Lise
L
Vadrot
Nathalie
N
Alexia
Catherine
C
Sadji-Ouatas
Zahia
Z
Bringuier
Annie-France
AF
Feldmann
Gérard
G
Pessayre
Dominique
D
Reyl-Desmars
Florence
F
D017209:Apoptosis / Q000187:drug effects*; D053143:Caspase 2; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002463:Cell Membrane Permeability / Q000187:drug effects; D002945:Cisplatin / Q000633:toxicity; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000378:metabolism; D004317:Doxorubicin / Q000633:toxicity; D005472:Fluorouracil / Q000633:toxicity*; D006801:Humans; D008928:Mitochondria / Q000378:metabolism*; D051336:Mitochondrial Membranes / Q000187:drug effects / Q000378:metabolism; D009153:Mutagens / Q000633:toxicity*; D009687:Nuclear Proteins / Q000172:deficiency / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding; D051745:Protein Kinase C-delta / Q000235:genetics / Q000378:metabolism*; D016315:Proto-Oncogene Proteins c-abl / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000378:metabolism; D051020:bcl-X Protein / Q000378:metabolism; D019014:fas Receptor / Q000378:metabolism
D004268:DNA-Binding Proteins; D009153:Mutagens; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D051020:bcl-X Protein; D019014:fas Receptor; D004317:Doxorubicin; D016315:Proto-Oncogene Proteins c-abl; D051745:Protein Kinase C-delta; C506433:CASP9 protein, human; D053143:Caspase 2; D053453:Caspase 9; D020169:Caspases; D002945:Cisplatin; D005472:Fluorouracil