Human pancreatic cancer cells disable function of Fas receptors at severallevels in Fas signal transduction pathway

The aims of this study were to evaluate the functional expression of Fas re ceptors (Fas) in human pancreatic cancer cell lines; Capan-1, AsPC-1, BxPC- 3, PANC-1, and MIA PaCa-2 and to search for the mechanisms of receptor-medi ated inhibition of Fas signaling in these cells. Despite the expression of Pas receptors at considerable levels, exposure of these cells to agonistic Fas antibodies (500 ng/ml) induced only minimal apoptosis in 4 cell lines. The mechanisms allowing resistance to Fas-mediated apoptosis are complex. U sing RT-PCR, we identified molecules which might counteract the apoptogenic signal at several levels of Fas signal transduction pathway. The most stri king findings were the overexpression of Fas decoy receptors (DcR3), Fas as sociated phosphatase-1 (FAP-1), and FLICE-inhibitory protein (c-FLIP) in th e resistant cell lines as well as in pancreatic cancer surgical specimens. In conclusion, pancreatic cancer cells express three molecules that can abr ogate Fas function at different levels of Fas signaling cascade, resulting in resistance to Fas-mediated apoptosis, and this may promote the progressi on of this malignancy.