title: Differential involvement of the CD95 (Fas/APO-1) receptor/ligand system on apoptosis induced by the wild-type p53 gene transfer in human cancer cells.
abstract: The CD95 (Fas/APO-1) system regulates a number of physiological and pathological processes of cell death. The ligand for CD95 induces apoptosis in sensitive target cells by interacting with a transmembrane cell surface CD95 receptor. We previously reported that the recombinant adenovirus-mediated transfer of the wild-type p53 gene caused apoptotic cell death in a variety of human cancer cells. To better understand the mechanism responsible for this cell death signaling, we have investigated the potential involvement of the CD95 receptor/ligand system in p53-mediated apoptosis. The transient expression of the wild-type p53 gene upregulated the CD95 ligand mRNA as well as protein expression in H1299 human lung cancer cells deficient for p53 and in DLD-1 and SW620 human colon cancer cells with mutated p53, all of which constitutively expressed CD95 receptor as shown by a flow cytometric analysis, and induced rapid apoptotic cell death as early as 24 h after gene transfer. However, the sensitivity to the cytolytic effect of agonistic anti-CD95 antibody (CH11) varied among these cell lines: CH11 induced apoptosis in H1299 cells, but not in DLD-1 and SW620 cells despite their abundant CD95 receptor expression, suggesting that the CD95 receptors on DLD-1 and SW620 cells might be inactivated. In addition, an antagonistic anti-CD95 ligand antibody (4H9) that interfered with the CD95-receptor-ligand interaction partially reduced the apoptosis induced by the wild-type p53 gene transfer in H1299 cells, whereas apoptosis of DLD-1 and SW620 cells occurred in the presence of 4H9. Taken together, these findings led us to conclude that the CD95 receptor/ligand system is differentially involved in p53-mediated apoptosis, suggesting that the restoration of the wild-type p53 function may mediate apoptosis through CD95 receptor/ligand interactions as well as an alternative pathway.
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000473:pathology*; D000260:Adenoviruses, Human / Q000235:genetics; D000920:Antibody-Dependent Cell Cytotoxicity; D017209:Apoptosis / Q000235:genetics / Q000502:physiology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000473:pathology*; D003110:Colonic Neoplasms / Q000235:genetics / Q000473:pathology*; D003587:Cytomegalovirus / Q000235:genetics; D053222:Fas Ligand Protein; D015972:Gene Expression Regulation, Neoplastic; D016158:Genes, p53; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000473:pathology*; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D012334:RNA, Neoplasm / Q000096:biosynthesis / Q000235:genetics; D015398:Signal Transduction / Q000502:physiology*; D014162:Transfection; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000502:physiology*; D019014:fas Receptor / Q000502:physiology*