Wild-type p53 induced sensitization of mutant p53 TNF-resistant cells: role of caspase-8 and mitochondria.
In the present study, we have investigated the mechanisms by which the restoration of wild-type (wt) p53 functions in p53 mutant cells increases their susceptibility to the cytotoxic action of tumor necrosis factor (TNF). Our data indicate that the resistance of p53-mutated cl.1001 cells to TNF-induced cell death was not due to a defect in the expression of TRADD and FADD, yet correlated with a reduced caspase-8 activation as well as a deficient mitochondrial membrane permeabilization. Moreover, cl.1001 cells failed to translocate the mitochondrial AIF and cytochrome c to the nucleus and to the cytosol, respectively, in response to TNF. Sensitization of these cells, following infection with a recombinant adenovirus encoding wtp53, to TNF-induced cytotoxicity resulted in the restoration of caspase-8 cleavage and the reestablishment of mitochondrial signs of apoptosis. These findings suggest that the cross-talk between p53 and TNF-induced cell death depends on mitochondria and that the combination of TNF and Adwtp53 may be a potential strategy to sensitize mutant p53 TNF-resistant tumors to the cytotoxic action of this cytokine.
Ameyar-Zazoua
Maya
M
INSERM U487, "Cytokines et Immunologie des Tumeurs Humaines," Institut Gustave Roussy, Villejuif 94805, France.
Larochette
Nathanaël
N
Dorothée
Guillaume
G
Daugas
Eric
E
Haddada
Hedi
H
Gouloumet
Vanessa
V
Métivier
Didier
D
Stancou
Rodica
R
Mami-Chouaib
Fathia
F
Kroemer
Guido
G
Chouaib
Salem
S
D000256:Adenoviridae / Q000235:genetics; D051033:Apoptosis Inducing Factor; D029681:Arabidopsis Proteins; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000378:metabolism* / Q000628:therapy; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects; D003574:Cytochrome c Group / Q000378:metabolism; D004351:Drug Resistance; D044943:Fatty Acid Desaturases / Q000235:genetics / Q000378:metabolism; D005420:Flavoproteins / Q000378:metabolism; D005434:Flow Cytometry; D005799:Genes, Dominant; D006801:Humans; D007473:Ion Channels / Q000187:drug effects*; D008564:Membrane Potentials / Q000187:drug effects; D008565:Membrane Proteins / Q000378:metabolism; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D047990:TNF Receptor-Associated Factor 1; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000166:cytology / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism* / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology
C494829:AIFM1 protein, human; D051033:Apoptosis Inducing Factor; D029681:Arabidopsis Proteins; D003574:Cytochrome c Group; D005420:Flavoproteins; D007473:Ion Channels; D008565:Membrane Proteins; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D011506:Proteins; D017382:Reactive Oxygen Species; D047990:TNF Receptor-Associated Factor 1; D014409:Tumor Necrosis Factor-alpha; D016159:Tumor Suppressor Protein p53; D044943:Fatty Acid Desaturases; C084083:Fad7 protein, Arabidopsis; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases