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

Malika Lasfer; Lise Davenne; Nathalie Vadrot; Catherine Alexia; Zahia Sadji-Ouatas; Annie-France Bringuier; Gérard Feldmann; Dominique Pessayre; Florence Reyl-Desmars

doi:10.1016/j.febslet.2006.03.089

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

FEBS Lett. 2006 May 15;580(11):2547-52. doi: 10.1016/j.febslet.2006.03.089. Epub 2006 Apr 12.

Authors

Malika Lasfer¹, Lise Davenne, Nathalie Vadrot, Catherine Alexia, Zahia Sadji-Ouatas, Annie-France Bringuier, Gérard Feldmann, Dominique Pessayre, Florence Reyl-Desmars

Affiliation

¹ INSERM, U773, Equipe 5, Centre de Recherche Bichat Beaujon CRB3, BP416, F-75018 Paris, France.

PMID: 16631755
DOI: 10.1016/j.febslet.2006.03.089

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.

MeSH terms

Apoptosis / drug effects*
Caspase 2
Caspase 9
Caspases / metabolism
Cell Line, Tumor
Cell Membrane Permeability / drug effects
Cisplatin / toxicity
DNA-Binding Proteins / deficiency
DNA-Binding Proteins / metabolism
Doxorubicin / toxicity
Fluorouracil / toxicity*
Humans
Mitochondria / metabolism*
Mitochondrial Membranes / drug effects
Mitochondrial Membranes / metabolism
Mutagens / toxicity*
Nuclear Proteins / deficiency
Nuclear Proteins / metabolism
Phosphorylation / drug effects
Protein Binding
Protein Kinase C-delta / genetics
Protein Kinase C-delta / metabolism*
Proto-Oncogene Proteins c-abl / genetics
Proto-Oncogene Proteins c-abl / metabolism*
RNA, Small Interfering / genetics
Reactive Oxygen Species / metabolism
Tumor Suppressor Protein p53 / deficiency
Tumor Suppressor Protein p53 / metabolism
Tumor Suppressor Proteins / deficiency
Tumor Suppressor Proteins / metabolism
bcl-X Protein / metabolism
fas Receptor / metabolism

Substances

DNA-Binding Proteins
Mutagens
Nuclear Proteins
RNA, Small Interfering
Reactive Oxygen Species
Tumor Suppressor Protein p53
Tumor Suppressor Proteins
bcl-X Protein
fas Receptor
Doxorubicin
Proto-Oncogene Proteins c-abl
Protein Kinase C-delta
CASP9 protein, human
Caspase 2
Caspase 9
Caspases
Cisplatin
Fluorouracil