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LIVER AND BILIARY TRACT

Tauroursodeoxycholate inhibits human cholangiocarcinoma growth via Ca²⁺-, PKC-, and MAPK-dependent pathways

¹ Internal Medicine and ²Medical Physiology and ³Division of Research and Education, Scott & White Hospital and The Texas A&M University System Health Science Center, College of Medicine, and ⁴Central Texas Veterans Health Care System, Temple, Texas 76504

Submitted 24 June 2003 ; accepted in final form 26 December 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 concentration- and time-dependent manners. TUDCA inhibition of cholangiocarcinoma growth was blocked by BAPTA-AM, an intracellular Ca²⁺ concentration ([Ca²⁺]_i) chelator, and H7, a PKC- inhibitor. TUDCA increased [Ca²⁺]_i and membrane translocation of the Ca²⁺-dependent PKC- in 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 PKC- but independent from Raf proteins and MAPK p38 and JNK/stress-activated protein kinases. TUDCA may be important for the treatment of cholangiocarcinoma.

bile acids; bile ducts; cyclic adenosine monophosphate; cancer; mitosis

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