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Am J Physiol Gastrointest Liver Physiol (December 30, 2003). doi:10.1152/ajpgi.00270.2003
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Submitted on June 24, 2003
Accepted on December 26, 2003

TAUROURSODEOXYCHOLATE INHIBITS HUMAN CHOLANGIOCARCINOMA GROWTH VIA CA2+-, PKC,- AND MAPK-DEPENDENT PATHWAYS

Gianfranco Alpini1, Noriatsu Kanno2, Jo Lynne Phinizy3, Shannon Glaser3, Heather Francis3, Silvia Taffetani3, and Gene LeSage4*

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

* To whom correspondence should be addressed. E-mail: Gene.LeSage{at}uth.tmc.edu.

Tauroursodeoxycholic acid (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 a concentration- and time-dependent manner. TUDCA inhibition of cholangiocarcinoma growth was blocked by BAPTA/AM, a [Ca2+]i chelator, and H7, a PKC-{alpha} inhibitor. TUDCA increased [Ca2+]i and membrane translocation of the Ca2+- dependent PKC-{alpha} 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-{alpha} but independent from Raf proteins and MAPK p38 and JNK/stress activated protein kinases. TUDCA may be important for the treatment of cholangiocarcinoma.




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