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This Article Full Text Full Text (PDF) All Versions of this Article: 295/6/G1150    most recent 90455.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by DeMorrow, S. Articles by Alpini, G. PubMed PubMed Citation Articles by DeMorrow, S. Articles by Alpini, G.

LIVER AND BILIARY TRACT

The endocannabinoid anandamide inhibits cholangiocarcinoma growth via activation of the noncanonical Wnt signaling pathway

¹Department of Medicine and ⁵Systems Biology and Translational Medicine, Texas A & M Health Science Center, College of Medicine, Temple, Texas; ²Digestive Disease Research Center and ³Division of Research and Education, Scott & White Hospital, Temple, Texas; ⁴Division of Anatomy, University "La Sapienza", Rome, Italy; ⁶Division of Research, Central Texas Veterans Health Care System, Temple, Texas; ⁷Department of Experimental Medicine, University of L'Aquila, L'Aquila, Italy; ⁸Texas Biosciences Institute, Temple College, Temple, Texas

Submitted 24 July 2008 ; accepted in final form 29 September 2008

Cholangiocarcinomas are cancers that have poor prognosis and limited treatment options. The noncanonical Wnt pathway is mediated predominantly by Wnt 5a, which activates a Ca²⁺-dependent pathway involving protein kinase C, or a Ca²⁺-independent pathway involving the orphan receptor Ror2 and subsequent activation of Jun NH₂-terminal kinase (JNK). This pathway is associated with growth-suppressing effects in numerous cell types. We have shown that anandamide decreases cholangiocarcinoma growth in vitro. Therefore, we determined the effects of anandamide on cholangiocarcinoma tumor growth in vivo using a xenograft model and evaluated the effects of anandamide on the noncanonical Wnt signaling pathways. Chronic administration of anandamide decreased tumor growth and was associated with increased Wnt 5a expression in vitro and in vivo. Treatment of cholangiocarcinoma cells with recombinant Wnt 5a decreased cell proliferation in vitro. Neither anandamide nor Wnt 5a affected intracellular calcium release, but both increased the JNK phosphorylation. Stable knockdown of Wnt 5a or Ror2 expression in cholangiocarcinoma cells abolished the effects of anandamide on cell proliferation and JNK activation. Modulation of the endocannabinoid system may be important in cholangiocarcinoma treatment. The antiproliferative actions of the noncanonical Wnt signaling pathway warrants further investigation to dissect the mechanism by which this may occur.

biliary tract cancer; receptor tyrosine kinase orphan receptor 2; Jun NH₂-terminal kinase