p53 potentiation of tumor cell susceptibility to CTL involves Fas and mitochondrial pathways.
In this study, we have investigated the mechanisms used by wild-type p53 (wtp53) to potentiate tumor cell susceptibility to CTL-mediated cell death. We report that wtp53 restoration in a human lung carcinoma cell line Institut Gustave Roussy (IGR)-Heu, displaying a mutated p53, resulted in up-regulation of Fas/CD95 receptor expression associated with an increase of tumor cell sensitivity to the autologous CTL clone, Heu127. However, when IGR-Heu cells were transfected with Fas cDNA, no potentiation to Heu127-mediated lysis was observed, indicating that induction of CD95 is not sufficient to sensitize target cells to CTL killing. Importantly, our data indicate that the effect of wtp53 on the Fas-mediated pathway involves a degradation of short cellular FLICE inhibitory protein resulting in subsequent caspase 8 activation. Furthermore, we demonstrate that wtp53 restoration also resulted in CTL-induced Bid translocation into mitochondria and a subsequent mitochondrial membrane permeabilization leading to cytochrome c release. These results indicate that tumor cell killing by autologous CTL can be enhanced by targeting degranulation-independent mechanisms via restoration of wtp53, a key determinant of apoptotic machinery regulation.
Thiery
Jérôme
J
Laboratoire Cytokines et Immunologie des Tumeurs Humaines, Unité 487 Institut National de la Santé et de la Recherche Médicale, Institut Fédératif de Recherche 54, Institut Gustave Roussy, Villejuif, France.
Abouzahr
Soraya
S
Dorothee
Guillaume
G
Jalil
Abdelali
A
Richon
Catherine
C
Vergnon
Isabelle
I
Mami-Chouaib
Fathia
F
Chouaib
Salem
S
D000260:Adenoviruses, Human / Q000235:genetics; D000276:Adjuvants, Immunologic / Q000235:genetics / Q000502:physiology*; D017209:Apoptosis / Q000276:immunology; D051023:BH3 Interacting Domain Death Agonist Protein; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D002352:Carrier Proteins / Q000378:metabolism; D053148:Caspase 3; D053179:Caspase 7; D053181:Caspase 8; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002999:Clone Cells; D045304:Cytochromes c / Q000378:metabolism; D003601:Cytotoxicity Tests, Immunologic; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D005822:Genetic Vectors; D006801:Humans; D007106:Immune Sera / Q000494:pharmacology; D007425:Intracellular Membranes / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008564:Membrane Potentials / Q000276:immunology; D008928:Mitochondria / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism; D010539:Permeability; D020033:Protein Isoforms / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000502:physiology*; D019014:fas Receptor / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology / Q000502:physiology*
D000276:Adjuvants, Immunologic; D051023:BH3 Interacting Domain Death Agonist Protein; C494814:BID protein, human; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; D002352:Carrier Proteins; D007106:Immune Sera; D047908:Intracellular Signaling Peptides and Proteins; D020033:Protein Isoforms; D016159:Tumor Suppressor Protein p53; D019014:fas Receptor; D045304:Cytochromes c; C505407:CASP3 protein, human; C505520:CASP7 protein, human; C505530:CASP8 protein, human; D053148:Caspase 3; D053179:Caspase 7; D053181:Caspase 8; D020169:Caspases