Amplified in breast cancer 1 enhances human cholangiocarcinoma growth and chemoresistance by simultaneous activation of Akt and Nrf2 pathways

Transcriptional coactivator amplified in breast cancer 1 (AIB1) plays important roles in the progression of several cancers such as prostate cancer, breast cancer, and hepatocellular carcinoma. However, its role in cholangiocarcinoma (CCA), a chemoresistant bile duct carcinoma with a poor prognosis, remains unclear. In this study we found that AIB1 protein was frequently overexpressed in human CCA specimens and CCA cell lines. Down-regulation of AIB1 induced the G2/M arrest and decreased the expression of mitosis-promoting factors including Cyclin A, Cyclin B, and Cdk1 through suppressing the Akt pathway, which resulted in inhibiting CCA cell proliferation. In addition, AIB1 enhanced the chemoresistance of CCA cells at least in part through up-regulating the expression of antiapoptotic protein Bcl-2. AIB1 regulated the expression of Bcl-2 in CCA cells through activating the Akt pathway as well as suppressing intracellular reactive oxygen species (ROS). AIB1 suppressed ROS by up-regulating antioxidants such as glutathione synthetase and glutathione peroxidase, which are targets of the NF-E2-related factor 2 (Nrf2), a critical transcription factor that regulates antioxidants, detoxification enzymes, and drug efflux proteins. AIB1 also increased the expression of another two Nrf2 targets, ABCC2 and ABCG2, to enhance drug efflux. AIB1 served as an essential coactivator for Nrf2 activation by physically interacting with Nrf2 to enhance its transcriptional activity. Conclusion: AIB1 plays an important role in proliferation and chemoresistance of CCA through simultaneous activation of Akt and Nrf2 pathways, suggesting that AIB1 is a potential molecular target for CCA treatment. (HEPATOLOGY 2012;55:18221831)