Anandamide exerts its antiproliferative actions on cholangiocarcinoma by activation of the GPR55 receptor

Abstract

Cholangiocarcinomas are devastating cancers of biliary origin with limited treatment options. It has previously been shown that the endocannabinoid anandamide exerts antiproliferative effects on cholangiocarcinoma independent of any known cannabinoid receptors, and via the stabilization of lipid rafts, thereby allowing the recruitment and activation of the Fas death receptor complex. Recently, GPR55 was identified as a putative cannabinoid receptor; therefore, the role of GPR55 in the antiproliferative effects of anandamide was evaluated. GPR55 is expressed in all cholangiocarcinoma cells and liver biopsy samples to a similar level as in non-malignant cholangiocytes. Treatment with either anandamide or the GPR55 agonist, O-1602 reduced cholangiocarcinoma cell proliferation in vitro and in vivo. Furthermore, knocking down the expression of GPR55 prevented the antiproliferative effects of anandamide. Coupled to these effects was an increase in JNK activity. The antiproliferative effects of anandamide could be blocked by pretreatment with a JNK inhibitor and the lipid raft disruptors β-methylcyclodextrin and fillipin III. Activation of GPR55 by anandamide or O-1602 increased the amount of Fas in the lipid raft fractions, which could be blocked by pretreatment with the JNK inhibitor. This data represent the first evidence that GPR55 activation by anandamide can lead to the recruitment and activation of the Fas death receptor complex and that targeting GPR55 activation may be a viable option for the development of therapeutic strategies to treat cholangiocarcinoma.

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 .…”

A Selective Antagonist Reveals a Potential Role of G Protein–Coupled Receptor 55 in Platelet and Endothelial Cell Function

“…GPR55 is highly abundant in the central nervous system as well as in intestine, bone marrow, spleen, platelets, and immune and endothelial cells (Sawzdargo et al, 1999;Ryberg et al, 2007;Waldeck-Weiermair et al, 2008;Pietr et al, 2009;Balenga et al, 2011a;Henstridge et al, 2011;Rowley et al, 2011). Moreover, GPR55 has been detected in a variety of cancer tissues and cancer cell lines (Ford et al, 2010;Andradas et al, 2011;Huang et al, 2011;Pineiro et al, 2011;Perez-Gomez et al, 2012). Several endogenous GPR55 signaling pathways have been described to date despite controversial findings concerning its agonists and antagonists (Balenga et al, 2011b).…”

The Cannabinoid Receptor CB1 Modulates the Signaling Properties of the Lysophosphatidylinositol Receptor GPR55

“…ELISA data were normalized and are mean Ϯ S.E. development of cancer (12)(13)(14)(15), bone formation (20), pain and inflammation (6,8,66). GPR55 activation and function is still controversial and seems to be highly cell system dependent.…”