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.

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