H. Shinohara et al., Fas drives cell cycle progression in glioma cells via extracellular signal-regulated kinase activation, CANCER RES, 60(6), 2000, pp. 1766-1772
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.