IFN-γ upregulates apoptosis-related molecules and enhances Fas-mediated apoptosis in human cholangiocarcinoma

Abstract

Human cholangiocarcinoma is a malignancy with no effective therapy and a poor prognosis. Previously, we demonstrated that cultured human cholangiocarcinoma cell lines heterogeneously express Fas on their surface, resulting in 2 subpopulations, Fas-high and Fas-low cells. Fas-low cells are resistant to apoptosis induced by Fas antibody and the calmodulin antagonists tamoxifen and trifluoperazine and are tumorigenic in nude mice (Pan et al., Am J Pathol 1999;155: 193-203). Here, we show that IFN-γ enhances apoptosis in both Fas-high and Fas-low cells. IFN-γ upregulates many apoptosis-related molecules, including Fas, caspase-3, caspase-4, caspase-7, caspase-8 and Bak, in both cell lines. Pretreatment with IFN-γ facilitated Fas-mediated caspase cleavage, cytochrome c release and Bax translocation. The ability of IFN-γ to inhibit tumorigenesis of Fas-low cells was demonstrated in nude mice. Intratumoral injection of IFN-γ decreased tumor volumes by 78%. These findings indicate that IFN-γ modulates the apoptotic pathway by upregulating apoptosis-related genes. This renders tumorigenic Fas-low cholangiocarcinoma cells nontumorigenic and sensitive to Fas apoptosis, thus representing a possible therapeutic modality. © 2002 Wiley-Liss, Inc.