THE FAS SIGNALING PATHWAY IS FUNCTIONAL IN COLON-CARCINOMA CELLS AND INDUCES APOPTOSIS

Fas is expressed in colonic epithelial cells and is also expressed in colon carcinomas, although its functional significance in the regulati on of apoptosis in cells outside of the immune system remains unknown. In this study, we determined the role of Fas signaling on cellular gr owth of cultured colon carcinoma cells and demonstrated apoptosis indu ced by a cytotoxic anti-Fas monoclonal antibody (CH-11) in cells of th e GC(3)/c1 lineage (GC(3)/c1, TS-, Thy4) but not in HCT116 or CaCo2 ce lls. Growth inhibition was detected at concentrations of CH-11 as low as 1 ng/ml, and clonogenic survival studies yielded IC50 values of 3-2 6 ng/ml. Cytotoxicity was inhibited by ZB4, a monoclonal antibody inhi bitory to Fas signaling. In addition, the survival factor Bcl-2, which has demonstrated inconsistent protective effects against Fas signalin g in other systems, was inhibitory to Fas-induced apoptosis in colon c arcinoma cells after adenoviral transduction. Fas was expressed at the highest levels in TS- and Thy4 cells, which were the most sensitive c ell lines to Fas-induced apoptosis. FAP-1, a protein tyrosine phosphat ase that interacts with the cytosolic negative regulatory domain of Fa s, was expressed in each cell line but did not correlate with sensitiv ity 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 res ponse to treatment with chemotherapeutic agents should be further expl ored.