title: The fas signaling pathway is functional in colon carcinoma cells and induces apoptosis.
abstract: Fas is expressed in colonic epithelial cells and is also expressed in colon carcinomas, although its functional significance in the regulation of apoptosis in cells outside of the immune system remains unknown. In this study, we determined the role of Fas signaling on cellular growth of cultured colon carcinoma cells and demonstrated apoptosis induced by a cytotoxic anti-Fas monoclonal antibody (CH-11) in cells of the GC3/c1 lineage (GC3/c1, TS-, Thy4) but not in HCT116 or CaCo2 cells. Growth inhibition was detected at concentrations of CH-11 as low as 1 ng/ml, and clonogenic survival studies yielded IC50 values of 3-26 ng/ml. Cytotoxicity was inhibited by ZB4, a monoclonal antibody inhibitory to Fas signaling. In addition, the survival factor Bcl-2, which has demonstrated inconsistent protective effects against Fas signaling in other systems, was inhibitory to Fas-induced apoptosis in colon carcinoma cells after adenoviral transduction. Fas was expressed at the highest levels in TS- and Thy4 cells, which were the most sensitive cell lines to Fas-induced apoptosis. FAP-1, a protein tyrosine phosphatase that interacts with the cytosolic negative regulatory domain of Fas, was expressed in each cell line but did not correlate with sensitivity to Fas-mediated apoptosis. These data have therefore identified a functional Fas pathway in colon carcinoma cells when Fas is expressed at high levels. Hence, the role of Fas signaling in the regulation of apoptosis in colon carcinoma cells and its role in influencing the response to treatment with chemotherapeutic agents should be further explored.
authors.affiliation: Department of Molecular Pharmacology, St. Jude Children's Research Hospital, 332 North Lauderdale, Memphis, Tennessee 38105, USA.
authors.forename: J A
authors.initials: JA
authors.lastname: Houghton
authors.forename: F G
authors.initials: FG
authors.lastname: Harwood
authors.forename: A A
authors.initials: AA
authors.lastname: Gibson
authors.forename: D M
authors.initials: DM
authors.lastname: Tillman
mesh_terms: D000230:Adenocarcinoma; D000911:Antibodies, Monoclonal / Q000633:toxicity; D017209:Apoptosis; D002352:Carrier Proteins / Q000235:genetics; D002470:Cell Survival; D003110:Colonic Neoplasms; D006801:Humans; D054595:Protein Tyrosine Phosphatase, Non-Receptor Type 13; D017027:Protein Tyrosine Phosphatases / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction; D013940:Thymidylate Synthase / Q000172:deficiency / Q000378:metabolism; D014407:Tumor Cells, Cultured; D019014:fas Receptor / Q000235:genetics / Q000276:immunology / Q000502:physiology*
chemical_list: D000911:Antibodies, Monoclonal; D002352:Carrier Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D019014:fas Receptor; D013940:Thymidylate Synthase; C516742:PTPN13 protein, human; D054595:Protein Tyrosine Phosphatase, Non-Receptor Type 13; D017027:Protein Tyrosine Phosphatases