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 wildtype 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 de®cient 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¯ow cytometric analysis, and induced rapid apoptotic cell death as early as 24 h after gene transfer. However, the sensitivity to the cytolytic e ect 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 ®ndings led us to conclude that the CD95 receptor/ligand system is di erentially 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.

Quantification and characterization of the bystander effect in prostate cancer cells following adenovirus-mediated FasL expression

“…However, it is important to note that these observations may be cell-line dependent because other reports indicate that p53 and HSVtk/GCV utilize non-Fas-mediated apoptotic death pathways as well. 17,18 In summary, the data presented in this paper demonstrate that AdGFPFasL TET infection induces bystander killing in certain PCa cell lines through an Fas-mediated mechanism. Currently, we are evaluating the use of FasL as gene therapy in animal models.…”

“…13 Bystander Fas-mediated apoptosis may have relevance in other cancer gene therapy strategies. HSVtk/GCV, 14,15 HSVtk/GCV plus IL-12, 16 and p53 17 have been shown to activate the Fas-mediated apoptotic death pathway. However, it is important to note that these observations may be cell-line dependent because other reports indicate that p53 and HSVtk/GCV utilize non-Fas-mediated apoptotic death pathways as well.…”

Kupffer cells of cirrhotic rat livers sensitize colon cancer cells to Fas-mediated apoptosis

“…FasR-resistance of colon cancer cells is thought to be involved in the mechanism of immune evasion, and associated with their metastatic phenotype (Möller et al, 1994;O'Connell et al, 1998;Yoong et al, 1999). Restoration of colon cancer cell sensitivity to Fas-mediated apoptosis is able to facilitate them to TIL-mediated killing, and has been proposed to be an effective immunotherapy for containing the malignancy (Tamura et al, 1995;Houghton et al, 1997;Micheau et al, 1997;Bonnotte et al, 1998;Fukazawa et al, 1999). Thus, sensitization of colon cancer cells to Fas-mediated apoptosis by cirrhotic Kupffer cells, as demonstrated in the present study presumably contributes to the immunologic impedance of cirrhotic livers against metastasis formation of colorectal cancers.…”

Accelerated degradation of cellular FLIP protein through the ubiquitin-proteasome pathway in p53-mediated apoptosis of human cancer cells

“…It is now widely accepted that apoptosis is a gene-directed process and associated with several messenger systems that regulate this process either positively or negatively. We previously reported that overexpression of the wild-type p53 (wt-p53) gene by recombinant, replication-de®cient viral vectors induced apoptosis in a variety of human cancer cells di ering in p53 status (Kagawa et al, 1997;Fukazawa et al, 1999). Numerous other studies have shown that p53 mediates its e ects by modulating the transcription of a number of cellular target genes (Levine, 1997).…”