Prostate apoptosis response-4 is expressed in normal cholangiocytes, is down-regulated in human cholangiocarcinoma, and promotes apoptosis of neoplastic cholangiocytes when induced pharmacologically

Prostate apoptosis response-4 (Par-4) is a tumor suppressor\r\nprotein that sensitizes cells to apoptosis; therefore, Par-4 modulation has therapeutic potential.\r\nNo data currently exist on Par-4 expression in cholangiocarcinoma (CCA). We evaluated the expression\r\nof Par-4 in normal and neoplastic cholangiocytes and the effects of its pharmacological or genetic modulation.\r\nThe study was performed in human and rat\r\nliver, CCA patient biopsies, and two CCA cell lines.\r\nPAR-4 was expressed in normal rat and human cholangiocytes, but its expression levels decreased in\r\nboth human CCA and CCA cell lines. In both intrahepatic and extrahepatic CCA, Par-4 expression (as\r\nshown by immunohistochemistry) was inversely correlated with markers of proliferation (eg, proliferating\r\ncellular nuclear antigen) and directly correlated with apoptotic markers (eg, Bax and Bax/BCL2 ratio).\r\nPar-4 expression was decreased during CCA cell proliferation\r\nbut was enhanced after apoptosis induction.\r\nPharmacological induction of Par-4 expression in CCA cell lines by diindolymethane or withaferin A\r\npromoted activation of apoptosis and inhibition of proliferation. In contrast, specific Par-4 silencing by\r\nsmall-interfering RNA determined activation of CCA cell line proliferation. Par-4 is expressed in rat and human cholangiocytes and is down-regulated in both human CCA\r\nand CCA cell lines. Par-4 protein levels decrease during cell\r\nproliferation but increase during apoptosis. Pharmacological\r\nor genetic induction of Par-4 determines apoptosis of CCA cells, suggesting Par-4 targeting as a CCA\r\ntreatment strategy.