Fas drives cell cycle progression in glioma cells via extracellular signal-regulated kinase activation

Recent studies have revealed that a variety of malignant tumors express Fas and/or its ligand Fast, However, tumor cells expressing Fas are not always susceptible to Fas-mediated cell death, and the biological significance of simultaneous expression of Fas and Fast in the same tumor is not known. In the present study, we addressed this question in three glioma cells lines, A-172, T98G, and YKG-1, which express both Fas and FasL endogenously and t heir Fas transfectants. We report here that: (a) in gliomas, [H-3]TdR incor poration was enhanced by anti-Fas IgM monoclonal antibody CB-ll and convers ely inhibited by anti-Fast monoclonal antibody NOK-2; (b) cross-linking of Fas with CH-11 drove both cell cycle progression and apoptosis as demonstra ted by the induction of the S-G(2) phase of DNA and RNA and fragmented nucl ei; (c) phosphorylation of extracellular signal-regulated kinase (ERK), but not of c-Jun NH2-terminal kinase or p38, was induced by cross-linking of F as; (d) a mitogen-activated protein kinase/ERK: kinase 1 (MEK1) inhibitor P D98059 completely blacked CH-11-induced ERK phosphorylation as well as cell cycle progression without affecting induction of apoptosis; and fe) a broa d-spectrum caspase inhibitor Z-Asp-CH2-DCB inhibited CH-11-induced ERK phos phorylation, cell cycle progression, and apoptosis, These results indicate that Fas-mediated caspase activation elicits tno independent cellular respo nses; one is to induce apoptosis and another is to promote cell cycle progr ession; the tatter is closely linked to the MEK-ERK pathway. Together, our data strongly suggest that Fast may play a role as an autocrine growth fact or in gliomas.