G protein‐coupled receptor GPR55 promotes colorectal cancer and has opposing effects to cannabinoid receptor 1

Abstract

The putative cannabinoid receptor GPR55 has been shown to play a tumor-promoting role in various cancers, and is involved in many physiological and pathological processes of the gastrointestinal (GI) tract. While the cannabinoid receptor 1 (CB 1 ) has been reported to suppress intestinal tumor growth, the role of GPR55 in the development of GI cancers is unclear. We, therefore, aimed at elucidating the role of GPR55 in colorectal cancer (CRC), the third most common cancer worldwide. Using azoxymethane (AOM)-and dextran sulfate sodium (DSS)-driven CRC mouse models, we found that GPR55 plays a tumor-promoting role that involves alterations of leukocyte populations, i.e. myeloid-derived suppressor cells and T lymphocytes, within the tumor tissues. Concomitantly, expression levels of COX-2 and STAT3 were reduced in tumor tissue of GPR55 knockout mice, indicating reduced presence of tumor-promoting factors. By employing the experimental CRC models to CB 1 knockout and CB 1 /GPR55 double knockout mice, we can further show that GPR55 plays an opposing role to CB 1 . We report that GPR55 and CB 1 mRNA expression are differentially regulated in the experimental models and in a cohort of 86 CRC patients. Epigenetic methylation of CNR1 and GPR55 was also differentially regulated in human CRC tissue compared to control samples. Collectively, our data suggest that GPR55 and CB 1 play differential roles in colon carcinogenesis where the former seems to act as oncogene and the latter as tumor suppressor.

GPR55-Mediated Effects in Colon Cancer Cell Lines

“…Since we had recently found that GPR55-deficient mice had a significantly lower tumor burden in various models of colorectal cancer [13], we investigated whether these effects were mediated by the epithelial cells. Therefore, we analyzed six commercially available colon cancer cell lines for their GPR55 expression.…”

“…The transfection was performed with Lipofectamine 2000 according to the manufacturer’s protocol. Transfected cells were selected with 4 mg/mL G418 (Life Technologies) 48 h after transfection, grown to confluence, and subsequently sorted on a FACSAria (BD Biosciences, Franklin Lakes, NJ, USA) as described previously [13]. Sorted cells were maintained as HCT116-GPR55 (HCT55) and SW480-GPR55 (SW55) in their respective media, which were supplemented with 0.5 mg/mL G418.…”

“…In squamous cell carcinomas, breast and pancreatic cancer, and in glioblastomas, GPR55 expression levels are upregulated, positively correlating with aggressiveness [10, 11]. In vivo, GPR55 promotes carcinogenesis in mouse models of skin, pancreatic, and colorectal cancer [10, 12, 13]. Furthermore, GPR55 expression has been demonstrated in several cancer cell lines, such as breast, prostate, ovarian, glioblastoma, and colon cancer cells [11, 14, 15].…”

“…We have recently found that GPR55 promotes colorectal carcinogenesis [13] and that serum LPI levels were increased in colorectal cancer patients [15]. We, therefore, set out to investigate whether LPI had direct effects on the proliferation of colon cancer cell lines and whether GPR55 overexpression would alter signal transduction in these cells.…”

Medical Cannabis and Cannabinoids: An Option for the Treatment of Inflammatory Bowel Disease and Cancer of the Colon?

“…However, it is unknown whether these changes actually correlate with the disease progress. With regard to CRC, in vitro data from colon cancer cell lines convincingly show antiproliferative effects of cannabinoids [19] and, in fact, models of CRC in knockout mice suggest an anti-oncogenic role for at least CB 1 [20,21]. With regard to CB 2 , however, studies in human CRC patients show that its expression correlates with a decreased survival [22].…”