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lüll Activation of the Fas-FasL signaling pathway by MDA-7/IL-24 kills human ovarian cancer cells Gopalan B; Litvak A; Sharma S; Mhashilkar AM; Chada S; Ramesh RCancer Res 2005[Apr]; 65 (8): 3017-24The tumor-suppressive activity of melanoma differentiation-associated gene-7 (mda-7), also known as interleukin 24 (IL-24), has been shown in a spectrum of human cancer cells in vitro and in vivo. However, mechanisms responsible for antitumor activity of mda-7 in human ovarian cancer cells have not been identified. We investigated the therapeutic activity and underlying mechanisms of adenovirus-mediated mda-7 gene (Ad-mda7) transfer in human ovarian cancer cells. Ad-mda7 treatment resulted in overexpression of MDA-7/IL-24 protein in both ovarian cancer and normal ovarian epithelial cells. However, Ad-mda7 significantly (P = 0.001) inhibited cell proliferation and induced apoptosis only in tumor cells and not in normal cells. Studies addressing the mechanism of action of Ad-mda7-induced tumor cell apoptosis revealed early activation of the transcription factors c-Jun and activating transcription factor 2, which in turn stimulated the transcription of an immediate downstream target, the death-inducer Fas ligand (FasL), and its cognate receptor Fas. Associated with the activation of Fas-FasL was the activation of nuclear factor kappaB and induction of Fas-associated factor 1, Fas-associated death domain, and caspase-8. Promoter-based reporter gene analyses showed that Ad-mda7 specifically activated the Fas promoter. Inhibition of Fas using small interfering RNA resulted in a significant decrease in Ad-mda7-mediated tumor cell death. Additionally, blocking of FasL with NOK-1 antibody abrogated Ad-mda7-mediated apoptosis. Collectively, these results show that Ad-mda7-mediated killing of human ovarian cancer cells involves activation of the Fas-FasL signaling pathway, a heretofore unrecognized mediator of MDA-7 apoptosis induction.|Adenoviridae/genetics[MESH]|Apoptosis/genetics/physiology[MESH]|Cell Cycle/genetics/physiology[MESH]|Cell Line, Tumor[MESH]|Cell Proliferation[MESH]|Fas Ligand Protein[MESH]|Female[MESH]|Gene Transfer Techniques[MESH]|Genes, Tumor Suppressor[MESH]|Genetic Therapy/methods[MESH]|Humans[MESH]|Interleukins/biosynthesis/*genetics[MESH]|Membrane Glycoproteins/antagonists & inhibitors/biosynthesis/genetics/*physiology[MESH]|Ovarian Neoplasms/genetics/metabolism/*pathology/*therapy[MESH]|Promoter Regions, Genetic[MESH]|Signal Transduction[MESH]|fas Receptor/biosynthesis/genetics/*physiology[MESH] |