IFN‐γupregulates apoptosis‐related molecules and enhances Fas‐mediated apoptosis in human cholangiocarcinoma

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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.