Abstract |
Recent studies have revealed that a variety of malignant tumors express Fas and/or its ligand FasL. However, tumor cells expressing Fas are not always susceptible to Fas-mediated cell death, and the biological significance of simultaneous expression of Fas and FasL 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 their Fas transfectants. We report here that: (a) in gliomas, [3H]TdR incorporation was enhanced by anti-Fas IgM monoclonal antibody CH-11 and conversely inhibited by anti-FasL monoclonal antibody NOK-2; (b) cross-linking of Fas with CH-11 drove both cell cycle progression and apoptosis as demonstrated by the induction of the S-G2 phase of DNA and RNA and fragmented nuclei; (c) phosphorylation of extracellular signal-regulated kinase (ERK), but not of c-Jun NH2-terminal kinase or p38, was induced by cross-linking of Fas; (d) a mitogen-activated protein kinase/ERK kinase 1 (MEK1) inhibitor PD98059 completely blocked CH-11-induced ERK phosphorylation as well as cell cycle progression without affecting induction of apoptosis; and (e) a broad-spectrum caspase inhibitor Z-Asp-CH2-DCB inhibited CH-11-induced ERK phosphorylation, cell cycle progression, and apoptosis. These results indicate that Fas-mediated caspase activation elicits two independent cellular responses; one is to induce apoptosis and another is to promote cell cycle progression; the latter is closely linked to the MEK-ERK pathway. Together, our data strongly suggest that FasL may play a role as an autocrine growth factor in gliomas.
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Authors | H Shinohara, H Yagita, Y Ikawa, N Oyaizu |
Journal | Cancer research
(Cancer Res)
Vol. 60
Issue 6
Pg. 1766-72
(Mar 15 2000)
ISSN: 0008-5472 [Print] United States |
PMID | 10749152
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Antibodies, Monoclonal
- Caspase Inhibitors
- Enzyme Inhibitors
- FASLG protein, human
- Fas Ligand Protein
- Flavonoids
- Membrane Glycoproteins
- RNA, Neoplasm
- Recombinant Fusion Proteins
- benzyloxycarbonyl-Asp-CH2OC(O)-2,6-dichlorobenzene
- fas Receptor
- Aspartic Acid
- Mitogen-Activated Protein Kinases
- Mitogen-Activated Protein Kinase Kinases
- Caspases
- 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one
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Topics |
- Animals
- Antibodies, Monoclonal
(pharmacology)
- Apoptosis
(drug effects)
- Aspartic Acid
(analogs & derivatives, pharmacology)
- Caspase Inhibitors
- Caspases
(metabolism)
- Cell Cycle
(drug effects, physiology)
- Cell Survival
(drug effects)
- Enzyme Activation
(drug effects)
- Enzyme Inhibitors
(pharmacology)
- Fas Ligand Protein
- Flavonoids
(pharmacology)
- Gene Expression Regulation, Neoplastic
(drug effects)
- Glioma
(genetics, pathology)
- Humans
- MAP Kinase Signaling System
- Membrane Glycoproteins
(biosynthesis, immunology, physiology)
- Mitogen-Activated Protein Kinase Kinases
(antagonists & inhibitors, metabolism)
- Mitogen-Activated Protein Kinases
(metabolism)
- RNA, Neoplasm
(drug effects, genetics, metabolism)
- Recombinant Fusion Proteins
(genetics, physiology)
- Signal Transduction
- Transfection
- Tumor Cells, Cultured
(cytology, drug effects, metabolism)
- fas Receptor
(genetics, immunology, physiology)
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