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

Abstract

Cholangiocarcinomas are cancers that have poor prognosis and limited treatment options. The noncanonical Wnt pathway is mediated predominantly by Wnt 5a, which activates a Ca(2+)-dependent pathway involving protein kinase C, or a Ca(2+)-independent pathway involving the orphan receptor Ror2 and subsequent activation of Jun NH(2)-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.

Cholangiocarcinoma: current knowledge and future perspectives consensus statement from the European Network for the Study of Cholangiocarcinoma (ENS-CCA)

“…Among neuroendocrine factors that either inhibit proliferation or induce apoptosis secretin, gastrin, γ-aminobutyric acid, endothelin-1 and the endocannabinoid anandamide have been described 103,104,[106][107][108][109][110][111] . Although the activation of histamine H 3 and H 4 receptors (HRH 3 and HRH 4 ) inhibits CCA growth, histamine itself is considered proliferative as it sustains CCA growth by forming an autocrine loop 112,113 .…”

Bile Acid Signaling Is Involved in the Neurological Decline in a Murine Model of Acute Liver Failure

“…A DDCT analysis was performed using vehicle-treated tissue or untreated primary neurons as controls for subsequent experiments. 31,32 Data for all experiments were expressed as mean relative mRNA levels AE SEM.…”

Overexpression of PDZK1IP1, EEF1A2 and RPL41 genes in intrahepatic cholangiocarcinoma

“…Notably, 4 upregulated genes were assigned to the significantly enriched Wnt signaling pathway and cytokine-cytokine receptor interaction pathway, respectively. The relevance of these pathways in cholangiocarcinoma or hepatocellular carcinoma has previously been confirmed by several studies (10,11).…”