Wild-type p53 induced sensitization of mutant p53 TNF-resistant cells: Role of caspase-8 and mitochondria

Maya Ameyar-Zazoua, Nathanaäl Larochette, Guillaume Dorothée, Eric Daugas, Hedi Haddada, Vanessa Gouloumet, Didier Métivier, Rodica Stancou, Fathia Mami-Chouaib, Guido Kroemer, Salem Chouaib

    Résultats de recherche: Contribution à un journalArticleRevue par des pairs

    23 Citations (Scopus)

    Résumé

    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 FAD D, 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.

    langue originaleAnglais
    Pages (de - à)219-227
    Nombre de pages9
    journalCancer Gene Therapy
    Volume9
    Numéro de publication3
    Les DOIs
    étatPublié - 1 janv. 2002

    Contient cette citation