Fas-mediated apoptosis in cholangiocarcinoma cells is enhanced by 3,3′-diindolylmethane through inhibition of AKT signaling and FLICE-like inhibitory protein

Academic Article

Abstract

  • 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 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 signalregulated kinase and nuclear factor-κB 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. Copyright © American Society for Investigative Pathology.
  • Digital Object Identifier (doi)

    Author List

  • Chen Y; Xu J; Jhala N; Pawar P; Zhu ZB; Ma L; Byon CH; McDonald JM
  • Start Page

  • 1833
  • End Page

  • 1842
  • Volume

  • 169
  • Issue

  • 5