TY - JOUR
T1 - Wild-type p53 induced sensitization of mutant p53 TNF-resistant cells
T2 - Role of caspase-8 and mitochondria
AU - Ameyar-Zazoua, Maya
AU - Larochette, Nathanaäl
AU - Dorothée, Guillaume
AU - Daugas, Eric
AU - Haddada, Hedi
AU - Gouloumet, Vanessa
AU - Métivier, Didier
AU - Stancou, Rodica
AU - Mami-Chouaib, Fathia
AU - Kroemer, Guido
AU - Chouaib, Salem
N1 - Funding Information:
We thank Drs V Dixit and ME Peter for providing us MCF7 / FADD DN cells and C15 monoclonal antibodies, respectively. This work has been supported by a special grant of the Ligue Nationale Contre le Cancer (to SC and GK), Association pour la Recherche sur le Cancer (Grants 5253 and 5129 to SC), and the European Commission (to GK). Ameyar Maya is the recipient of a fellowship from Association pour la Recherche sur le Cancer (ARC).
PY - 2002/1/1
Y1 - 2002/1/1
N2 - 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.
AB - 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.
KW - Caspase-8
KW - Mitochondria
KW - TNF
KW - p53
UR - http://www.scopus.com/inward/record.url?scp=85047697709&partnerID=8YFLogxK
U2 - 10.1038/sj.cgt.7700434
DO - 10.1038/sj.cgt.7700434
M3 - Article
C2 - 11896437
AN - SCOPUS:85047697709
SN - 0929-1903
VL - 9
SP - 219
EP - 227
JO - Cancer Gene Therapy
JF - Cancer Gene Therapy
IS - 3
ER -