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(American Journal of Pathology. 2006;169:1833-1842.)
© 2006 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2006.060234

Fas-Mediated Apoptosis in Cholangiocarcinoma Cells Is Enhanced by 3,3'-Diindolylmethane through Inhibition of AKT Signaling and FLICE-Like Inhibitory Protein

Yabing Chen^*, Jianmin Xu^*, Nirag Jhala^*, Pritish Pawar^*, Zeng B. Zhu^*, Liping Ma^*, Chang-Hyun Byon^* and Jay M. McDonald^*

From the Department of Pathology,^* University of Alabama at Birmingham; and the Veterans Administration Medical Center, Birmingham, Alabama

4Stimulation of Fas-mediated apoptosis has been promoted as a potential therapy for many cancers, including cholangiocarcinoma. We have previously reported that Fas-resistant, but not Fas-sensitive, cholangiocarcinoma cells are tumorigenic in nude mice. The present studies sought to identify molecular targets that promote Fas-mediated apoptosis in cholangiocarcinoma. We found that Fas-resistant cholangiocarcinoma cells exhibited increased constitutive phosphorylation of AKT compared with Fas-sensitive cells. Increased phosphorylation of AKT was also demonstrated in human cholangiocarcinoma tumors and was evident in a mouse xenograft cholangiocarcinoma model. Furthermore, we found that 3,3'-diindolylmethane (DIM), a vegetable autolysis product, promoted Fas-mediated apoptosis of cholangiocarcinoma cells. DIM inhibited phosphorylation of AKT and activation of FLICE-like-inhibitory-protein (FLIP). Inhibition of phos-phatidylinositol 3-kinase/AKT decreased FLIP activation and promoted Fas-mediated apoptosis. By contrast, adenovirus-mediated constitutively activated AKT protected cholangiocarcinoma cells from Fas-mediated apoptosis. Decreased activation of extracellular signal-regulated kinase and nuclear factor-B and increased activation of caspase-3, -8, and -9 were associated with inhibition of AKT and FLIP. These results support AKT and FLIP as potential molecular targets and DIM as a potent compound for cholangiocarcinoma intervention.

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