COMMENTARY The putative cannabinoid receptor GPR55 promotes cancer cell proliferation G Hu 1 , G Ren 2 and Y Shi 1,2 1 Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, China and 2 Department of Molecular Genetics, Microbiology and Immunology, Robert Wood Johnson Medical School-University of Medicine and Dentistry of New Jersey, Piscataway, NJ, USA Cannabinoids, the active ingredients in marijuana, have dramatic effects on various organ systems. They exert their effects through two receptor types: CB1, primarily located in the brain, and CB2, primarily located in the immune system. Vertebrates also produce their own cannabinoid-like substances called endocannabinoids, including anandamide and 2-arachidonoylglyceral. Interestingly, some effects of endocannabinoids could not be explained by the signals through either CB1 or CB2. Recently, the orphan G protein-coupled receptor 55 (GPR55) was proposed to be an atypical cannabinoid receptor. In this issue of Oncogene, two groups demonstrated that GPR55 is expressed in various cancer types in an aggressiveness-related manner, suggesting a novel cancer biomarker and a potential therapeutic target. Oncogene (2011) 30, 139–141; doi:10.1038/onc.2010.502; published online 8 November 2010 Cannabinoids were initially isolated from the plant Cannabis Sativa, and a great number of natural and synthetic active components have been subsequently identified as cannabinoid ligands. Cannabinoid receptors, CB1 and CB2, were identified based on their binding to cannabinoids (Das et al., 1995). However, plant cannabinoids are not a part of evolution of verte- brates, and the cannabinoid recep- tors are not made for getting ‘high’. Indeed, scientists have discovered endogenous ligands for these recep- tors, endocannabinoids including anandamide and 2-arachidonylgly- cerol (Devane et al., 1992; Mechou- lam et al., 1995; Sugiura et al., 1996). It has been recently proposed that the orphan G-protein couple receptor GPR55 is engaged and activated by lysophosphatidyl- inositol (LPI; Oka et al., 2010) and anandamide (Lauckner et al., 2008). 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 Onco- gene, two groups demonstrated that GPR55 is expressed in various cancer types in an aggressiveness- related manner and have a critical role in regulating cancer-cell prolif- eration (Andradas et al., 2011; Pin˜eiro et al., 2011). Since the identification and cloning of the orphan G-protein coupled receptor GPR55 in 1999, investigations on its biological and pharmacological role have also led to interests in employing GPR55 as a potential therapeutic target for various diseases (Sharir and Abood, 2010). GPR55 expression has been widely detected in the nervous system and peripheral tis- sues, including frontal cortex, cere- bellum, striatum, hypothalamus, brain stem, dorsal root ganglia neurons, spleen, tonsil, adrenal, bone, endothelial cells, large intes- tine and adipose tissue. The recently developed commercial antibodies against GPR55 will allow the detec- tion of the expression of GPR55 at the protein level in normal and tumor tissues. Although GPR55 could bind anandamide, it seems that LPI is the putative ligand of GPR55; activated downstream signaling was always observed when exogenous LPI was added into several types of cultured cells, which express transfected or native GPR55 (Oka et al., 2010; Sharir and Abood, 2010). Though the proposal that GPR55 is a true cannabinoid receptor remains controversial, it is still proper to consider GPR55 as an atypical cannabinoid receptor. The physiological and pharmaco- logical role of GPR55 remains poorly understood. Male GPR55 / mice show a significant increase in the volume and thickness of trabecular bone and the presence of unresorbed cartilage, suggesting a possible application of selective GPR55 antagonists to treating osteoporosis (Whyte et al., 2009). On the other hand, female GPR55 / mice were resistant to inflammatory and neuropathic pain (Staton et al., 2008). The increased circulating levels of LPI in patients with ovarian cancer and the pro-prolif- erative effects of LPI on Ras-trans- formed cell lines indicate a possible role of GPR55 in cancer progress. However, there had been no direct evidence until most recently when it was reported that the LPI-GPR55 Correspondence: Dr Y Shi, Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai Jiao Tong University School of Medicine, 225 South Chongqing Road, Shanghai 200025, China. E-mail: yufangshi@sibs.ac.cn Oncogene (2011) 30, 139–141 & 2011 Macmillan Publishers Limited All rights reserved 0950-9232/11 www.nature.com/onc