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The Putative Cannabinoid Receptor GPR55 Promotes Cancer Cell Proliferation

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The Putative Cannabinoid Receptor GPR55 Promotes Cancer Cell Proliferation Oncogene (2011) 30, 139–141 & 2011 Macmillan Publishers Limited All rights reserved 0950-9232/11 www.nature.com/onc COMMENTARY The putative cannabinoid receptor GPR55 promotes cancer cell proliferation GHu1, G Ren2 and Y Shi1,2 1Key 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 2Department 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 that various agonists of the classical tumor tissues. Although GPR55 from the plant Cannabis Sativa, cannabinoid receptors CB1 and could bind anandamide, it seems and a great number of natural and CB2 possess antitumor effects, and that LPI is the putative ligand synthetic active components have have been approved to treat cancer of GPR55; activated downstream been subsequently identified as or to eliminate the side effects of signaling was always observed cannabinoid ligands. Cannabinoid chemotherapy (Alexander et al., when exogenous LPI was added receptors, CB1 and CB2, were 2009; Oesch and Gertsch, 2009). into several types of cultured cells, identified based on their binding to Interestingly, in this issue of Onco- which express transfected or native cannabinoids (Das et al., 1995). gene, two groups demonstrated GPR55 (Oka et al., 2010; Sharir and However, plant cannabinoids are that GPR55 is expressed in various Abood, 2010). Though the proposal not a part of evolution of verte- cancer types in an aggressiveness- that GPR55 is a true cannabinoid brates, and the cannabinoid recep- related manner and have a critical receptor remains controversial, it is tors are not made for getting ‘high’. role in regulating cancer-cell prolif- still proper to consider GPR55 as Indeed, scientists have discovered eration (Andradas et al., 2011; an atypical cannabinoid receptor. endogenous ligands for these recep- Pin˜eiro et al., 2011). The physiological and pharmaco- tors, endocannabinoids including Since the identification and logical role of GPR55 remains anandamide and 2-arachidonylgly- cloning of the orphan G-protein poorly understood. Male GPR55À/ cerol (Devane et al., 1992; Mechou- coupled receptor GPR55 in 1999, À mice show a significant increase lam et al., 1995; Sugiura et al., investigations on its biological and in the volume and thickness of 1996). It has been recently proposed pharmacological role have also led trabecular bone and the presence that the orphan G-protein couple to interests in employing GPR55 of unresorbed cartilage, suggesting receptor GPR55 is engaged and as a potential therapeutic target a possible application of selective activated by lysophosphatidyl- for various diseases (Sharir and GPR55 antagonists to treating inositol (LPI; Oka et al., 2010) and Abood, 2010). GPR55 expression osteoporosis (Whyte et al., 2009). anandamide (Lauckner et al., 2008). has been widely detected in the On the other hand, female GPR55/ In addition to their dramatic effects nervous system and peripheral tis- mice were resistant to inflammatory on the nervous, immune and other sues, including frontal cortex, cere- and neuropathic pain (Staton et al., systems, recent studies have shown bellum, striatum, hypothalamus, 2008). The increased circulating brain stem, dorsal root ganglia levels of LPI in patients with Correspondence: Dr Y Shi, Key Laboratory neurons, spleen, tonsil, adrenal, ovarian cancer and the pro-prolif- of Stem Cell Biology, Institute of Health bone, endothelial cells, large intes- erative effects of LPI on Ras-trans- Sciences, Shanghai Institutes for Biological tine and adipose tissue. The recently formed cell lines indicate a possible Sciences, Chinese Academy of Sciences, developed commercial antibodies role of GPR55 in cancer progress. Shanghai Jiao Tong University School of against GPR55 will allow the detec- However, there had been no direct Medicine, 225 South Chongqing Road, Shanghai 200025, China. tion of the expression of GPR55 at evidence until most recently when it E-mail: [email protected] the protein level in normal and was reported that the LPI-GPR55 Putative cannabinoid receptor GPR55 GHuet al 140 signaling pathway played a role in This demonstration of pro-prolif- of CB1/CB2 to GPR55, it is reason- modulating migration, orientation erative effects of GPR55 on cancer able to propose that examination and polarization of breast cancer cells contributes to a better under- of the coexpression status of CB1/ cells MDA-MB-231 and MCF-7 standing of tumor progress and CB2 and GPR55 should be a novel (Ford et al., 2010). better development of therapeutic approach for selecting cancer types The current two studies provided strategy for cancer. Many cannabi- that are more suitable for a specific strong evidence that GPR55 pro- noid preparations have been suc- therapy. motes cancer cell proliferation cessfully used for treating As the investigation of the phy- (Andradas et al., 2011; Pin˜eiro neuropathic pain, multiple sclerosis, siological and pathological func- et al., 2011). In one study, Andradas schizophrenia and various other tions of GPR55 is just at the et al. found that most human cancer disorders. Based on their antiproli- beginning, many questions remain cell lines contain detectable levels of ferative, antimetastatic, antiangio- to be answered. How many types of GPR55 mRNA. Higher GPR55 genic and pro-apoptotic effects, the cancer cells express GPR55 in a expression is associated with more CB1/CB2 agonists were recently cancer progress-dependent manner? aggressive phenotypes (higher proposed to be novel agents for Would GPR55 expression in im- histological grades and higher pro- the treatment of various cancer mune system functionally regulate liferative rates) in human breast types. More importantly, canabi- inflammatory immune responses, tumors, pancreatic tumors and noids are effective in eliminating especially under stress conditions? glioblastomas. Overexpression of side effects of chemotherapy, such Are there any other endogenous GPR55 enhanced proliferation as nausea, vomiting and lack of ligands for GPR55? Does the func- of HEK293 cells via extracellular appetite (Alexander et al., 2009). tion of cannabinoid ligands on signal-regulated protein kinase. Delta-9-tetrahydrocannabinol (THC), GPR55 in normal tissues depend Moreover, knockdown of GRP55 the most active component of phy- on cell types and/or environment? expression in T98G glioma cells tocannabinoids and most com- And does the expression level of reduced tumor growth. In another monly used preparation of GPR55 and its overlapping expres- study, Pin˜eiro et al. demonstrated cannabinoids in clinical settings, sion with CB1/CB2 underlie the GPR55 expression in several pros- has been shown to have protumor divergent effects? With the develop- tate and ovarian cancer cell lines, and antitumor effects in a dose- or ment of selective agonists/antago- and that GPR55 has a critical cell type-dependent manner in nists and antibodies (especially role in LPI-induced cancer growth in vitro and in vivo models (Alex- those suitable for flow cytometry) and activation of intracellular ander et al., 2009). Interestingly, as well as gene-modified mice, these signaling pathways. Furthermore, THC has been shown to be a questions are sure to be answered in in prostate cancer cells, LPI was GPR55 agonist in some studies but the near future. shown to synergize with cPLA2 not in others (Sharir and Abood, and extracellular exportation of 2010). Given that cannabinoids LPI by the ABCC1 transporter exhibit antitumor effects as CB1/ Conflict of interest is responsible for the activation CB2 agonists and protumor effects of GPR55 and promotion of cell as GPR55 agonists, and different The authors declare no conflict of proliferation. cancer cells express different ratio interest. References Alexander A, Smith PF, Rosengren RJ. (2010). A role for L-alpha-lysophosphati- Oka S, Kimura S, Toshida T, Ota R, (2009). Cannabinoids in the treatment of dylinositol and GPR55 in the modulation Yamashita A, Sugiura T. (2010). Lysopho- cancer. Cancer Lett 285: 6–12. of migration, orientation and polarization sphatidylinositol induces rapid phosphor- Andradas C, Caffarel MM, Pe´rez-Go´mez E, of human breast cancer cells. Br J ylation of p38 mitogen-activated protein Salazar M, Lorente M, Velasco G et al. Pharmacol 160: 762–771. kinase and activating transcription factor (2011). The orphan G protein-coupled Lauckner JE, Jensen JB, Chen HY, Lu HC, 2 in HEK293 cells expressing
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