IFN-γupregulates apoptosis-related molecules and enhances Fas-mediated apoptosis in human cholangiocarcinoma
Article first published online: 13 JUN 2002
Copyright © 2002 Wiley-Liss, Inc.
International Journal of Cancer
Volume 100, Issue 4, pages 445–451, 1 August 2002
How to Cite
Ahn, E.-Y., Pan, G., Vickers, S. M. and McDonald, J. M. (2002), IFN-γupregulates apoptosis-related molecules and enhances Fas-mediated apoptosis in human cholangiocarcinoma. Int. J. Cancer, 100: 445–451. doi: 10.1002/ijc.10516
- Issue published online: 27 JUN 2002
- Article first published online: 13 JUN 2002
- Manuscript Accepted: 1 MAY 2002
- Manuscript Revised: 28 MAR 2002
- Manuscript Received: 22 OCT 2001
- National Institutes of Health
- Dept. of Veterans Affairs. Grant Numbers: CA72823, CA72823-S
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.