The orphan G protein-coupled receptor GPR55 promotes cancer cell proliferation via ERK

Abstract

GPR55 is an orphan G protein-coupled receptor that may be engaged by some lipid ligands such as lysophosphatidylinositol and cannabinoid-type compounds. Very little is known about its expression pattern and physio-pathological relevance, and its pharmacology and signaling are still rather controversial. Here we analyzed the expression and function of GPR55 in cancer cells. Our data show that GPR55 expression in human tumors from different origins correlates with their aggressiveness. Moreover, GPR55 promotes cancer cell proliferation, both in cell cultures and in xenografted mice, through the overactivation of the extracellular signal-regulated kinase cascade. These findings reveal the importance of GPR55 in human cancer, and suggest that it could constitute a new biomarker and therapeutic target in oncology.

Modulation of l-α-Lysophosphatidylinositol/GPR55 Mitogen-activated Protein Kinase (MAPK) Signaling by Cannabinoids

“…GPR55-mediated MAPK Signaling-Importantly, our findings demonstrate that LPI-induced ERK1/2 phosphorylation is controlled, at least in part, by ROCK, supporting the role for G␣ 12/13 in LPI signaling and indicating cross-talk between MAPK and Rho GTPases signaling, which is in line with Andradas et al (11). Such cross-talk may be communicated via the serine/threonine kinase Raf family, of which the expression level of the oncogene B-Raf in turn controls the stimulation of ROCK (60).…”

“…Importantly, GPR55-induced ERK1/2 phosphorylation regulates human cancer cell migration in vitro and proliferation in vivo (3,8,11). It also appears to govern the maintenance of persistent inflammatory pain (22,23).…”

“…Subsequently, studies have established that the endogenous lysophospholipid LPI 2 activates GPR55 (3)(4)(5)(6)(7)(8)(9)(10). In certain cancer cell lines, GPR55 is highly expressed, and LPI mediates increased cell migration, invasion, and proliferation (3,8,11). Moreover, increased circulating levels of LPI have been found in cancer patients and are associated with a poor prognosis (12).…”

“…Among these factors, the most investigated is ERK1/2 (5-9, 11, 15-17). Other nuclear transcription factors recruited by GPR55 activation are nuclear factor of activated T cells (NFAT) (9,13), cAMP-response element-binding protein (CREB), nuclear factor -light chain enhancer of activated T cells (NF-B) (4, 9, 13), p38 MAPK (18), and Akt serine/threonine protein kinase (8,11).…”

The putative cannabinoid receptor GPR55 promotes cancer cell proliferation

“…In addition to their dramatic effects on the nervous, immune and other systems, recent studies have shown that various agonists of the classical cannabinoid receptors CB1 and CB2 possess antitumor effects, and have been approved to treat cancer or to eliminate the side effects of chemotherapy (Alexander et al, 2009;Oesch and Gertsch, 2009). Interestingly, in this issue of Oncogene, two groups demonstrated that GPR55 is expressed in various cancer types in an aggressivenessrelated manner and have a critical role in regulating cancer-cell proliferation (Andradas et al, 2011;Pin˜eiro et al, 2011).…”