The Novel Cannabinoid Receptor GPR55, Inhibits Cholangiocarcinoma Growth

[Truth Seeker]

Anandamide (AEA) inhibits cholangiocarcinoma (CCA) growth via stabilization of lipid rafts, and the activation of death receptors. GPR55 has been identified as a putative cannabinoid receptor that may be activated by AEA, although its effects on CCA proliferation are unknown. Our aims were to evaluate the effects of GPR55 activation on CCA growth and the downstream signaling cascade. GPR55 was expressed in CCA cells and biopsy samples to a similar level as the non-malignant counterparts. The GPR55 agonists O-1602 or AEA reduced viability in vitro and tumor growth in vivo. Activation of GPR55 by AEA or O-1602 activated JNK, which was required for their antiproliferative actions. Pretreatment with the lipid raft disruptors prevented these antiproliferative effects. Lipid rafts were isolated from CCA cells treated with AEA or O-1602 and immunoblotting of the resulting fractions reveals both GPR55 and Fas are recruited into lipid rafts after AEA and O-1602. Transfection of CCA cells with FADD shRNA prevented the antiproliferative effects of GPR55 receptor activation. Activation of GPR55 exerts antiproliferative effects on CCA via the activation of a JNK-mediated pathway, resulting in the recruitment of Fas into lipid raft membrane structures. Specific targeting of GPR55 may prove to be useful in designing adjunct therapies for the treatment of CCA. This work was supported by NIH K01 and R03 awards.

Source: The novel cannabinoid receptor GPR55, inhibits cholangiocarcinoma growth -- DeMorrow et al. 25 (1): 1117.3 -- The FASEB Journal