Tauroursodeoxycholate inhibits human cholangiocarcinoma growth via Ca -, PKC-, and MAPK-dependent pathways

Alpini, Gianfranco, Noriatsu Kanno, Jo Lynne Phinizy, Shannon Glaser, Heather Francis, Silvia Taffetani, and Gene LeSage. Tauroursodeoxycholate inhibits human cholangiocarcinoma growth via Ca -, PKC-, and MAPK-dependent pathways. Am J Physiol Gastrointest Liver Physiol 286: G973–G982, 2004. First published December 30, 2003; 10.1152/ajpgi.00270.2003.—Tauroursodeoxychate (TUDCA) is used for the treatment of cholangiopathies including primary sclerosing cholangitis, which is considered the primary risk factor for cholangiocarcinoma. The effect of TUDCA on cholangiocarcinoma growth is unknown. We evaluated the role of TUDCA in the regulation of growth of the cholangiocarcinoma cell line Mz-ChA-1. TUDCA inhibited the growth of Mz-ChA-1 cells in concentrationand time-dependent manners. TUDCA inhibition of cholangiocarcinoma growth was blocked by BAPTA-AM, an intracellular Ca concentration ([Ca ]i) chelator, and H7, a PKCinhibitor. TUDCA increased [Ca ]i and membrane translocation of the Ca -dependent PKCin Mz-ChA-1 cells. TUDCA inhibited the activity of MAPK, and this inhibitory effect of TUDCA was abrogated by BAPTA-AM and H7. TUDCA did not alter the activity of Raf-1 and B-Raf and the phosphorylation of MAPK p38 and JNK/ stress-activated protein kinase. TUDCA inhibits Mz-ChA-1 growth through a signal-transduction pathway involving MAPK p42/44 and PKCbut independent from Raf proteins and MAPK p38 and JNK/stress-activated protein kinases. TUDCA may be important for the treatment of cholangiocarcinoma.