title: Fas-mediated apoptosis in cholangiocarcinoma cells is enhanced by 3,3'-diindolylmethane through inhibition of AKT signaling and FLICE-like inhibitory protein.
abstract: Stimulation 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 phosphatidylinositol 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-kappaB 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.
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, LHRB 511, 1530 3rd Ave. South, Birmingham, AL 35294, USA. ybchen@path.uab.edu
authors.forename: Yabing
authors.initials: Y
authors.lastname: Chen
authors.forename: Jianmin
authors.initials: J
authors.lastname: Xu
authors.forename: Nirag
authors.initials: N
authors.lastname: Jhala
authors.forename: Pritish
authors.initials: P
authors.lastname: Pawar
authors.forename: Zeng B
authors.initials: ZB
authors.lastname: Zhu
authors.forename: Liping
authors.initials: L
authors.lastname: Ma
authors.forename: Chang-Hyun
authors.initials: CH
authors.lastname: Byon
authors.forename: Jay M
authors.initials: JM
authors.lastname: McDonald
mesh_terms: D000256:Adenoviridae / Q000378:metabolism; D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000037:antagonists & inhibitors*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D020169:Caspases / Q000378:metabolism; D018281:Cholangiocarcinoma / Q000473:pathology*; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D005799:Genes, Dominant; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects*; D023041:Xenograft Model Antitumor Assays; D019014:fas Receptor / Q000378:metabolism*
chemical_list: D016588:Anticarcinogenic Agents; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C491901:FAS protein, human; D007211:Indoles; D016328:NF-kappa B; D000081082:Phosphoinositide-3 Kinase Inhibitors; D019014:fas Receptor; C016517:indole-3-carbinol; D051057:Proto-Oncogene Proteins c-akt; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D020169:Caspases; C016392:3,3'-diindolylmethane