br Lysophosphatidylinositol LPI LPI is a

Lysophosphatidylinositol (LPI) LPI is a subspecies of lysophospholipid consisting of inositol as its head group, one glycerol molecule and one acyl chain (Piñeiro and Falasca, 2012). The biosynthesis of this lipid starts from Phosphatidylinositol (PI) and is catalysed by the enzymes phospholipase A that cleave PI to release fatty acids and LPI. There are two different enzymes, called PLA1 and PLA2, that can hydrolyse different positions in the glycerol moiety. As a consequence, PLA1 produces 2-Acyl LPI whereas PLA2 produces 1-Acyl LPI. Emerging data suggest a potential role for LPI in cancer. The hypothesis of a role for LPI in Ras-dependent tumours was first supported by the observations that malignant transformation of epithelial thyroid MMP-2/MMP-9 Inhibitor I and fibroblasts with the oncogene Ras led to the synthesis and release of LPI and that LPI induced proliferation of these cells (Falasca and Corda, 1994, Falasca et al., 1995). This was later supported by clinical evidence showing that patients with ovarian or peritoneal cancer have higher accumulated levels of lysophospholipids, including LPI, than healthy controls (Sutphen et al., 2004, Xiao et al., 2000). It is important to mention that the high levels of lysophospholipids were not due to an increase in the total levels of phospholipids, since no differences were found in total lipids in the ascites of these two populations. Furthermore, another strong link between LPI and cancer has been recently established. We have shown that LPI, together with its established receptor GPR55, is involved in an autocrine loop regulating the proliferation of prostate and ovarian cancer cells (Pineiro et al., 2011). In these cells, the enzyme cPLA2 synthesises a pool of intracellular LPI that is released by the transporter ABCC1. Once in the extracellular media, LPI activates GPR55 and the signalling cascades downstream the receptor, stimulating cell growth. This fact suggests that these cells may contribute to increase LPI levels in the plasma of patients with prostate cancer, in the same way as shown in patients with ovarian cancer (Xiao et al., 2000). It is then plausible to speculate that LPI may be used as a biomarker in prostate and ovarian cancer. It has been suggested that 2-Arachidonoyl-LPI is the most potent ligand of GPR55, although this study only showed a small difference in GPR55 activation between the different LPI species (Yamashita et al., 2013). On the other hand, another study specifically used 1-acyl-LPI to demonstrate the role of LPI in breast cancer (Ford et al., 2010). The specific role of each LPI species still remains to be addressed.
GPR55 GPR55 is a GPCR that has been proposed to be part of the endocannabinoid system (CB1 and CB2) but whose pharmacology is still under investigation. GPR55 displays low amino acid homology with CB1 (13.5%) and CB2 (14.4%) (Baker et al., 2006) and the closest homologs to GPR55 are LPAR6 (29%), GPR23 (30%), GPR35 (27%) and the chemokine receptor CCR4 (24%) (Sawzdargo et al., 1999). GPR55 mRNA was found to be expressed in different tissues of the body such as brain, spleen, bones and in cells such as adipocytes, gastrointestinal tract cells and islets of Langerhans. Consequently, numerous studies have revealed various physiological functions for this receptor.
Conclusions Emerging evidences suggest that the LPI receptor GPR55 plays a key role in different cancer types. In particular, a link between GPR55 and cancer has been investigated in prostate, ovarian, glioblastoma, breast, skin and pancreatic cancer. Therefore, current research suggests that LPI/GPR55-axis blockade by GPR55 antagonists may represent a novel strategy to counteract cancer progression. The GPR55 antagonist CBD has been shown to possess anti-cancer activity in several cancer models. Nevertheless, none of these studies have assessed whether this antineoplastic property is due to a specific GPR55 targeting. Several synthetic GPR55 antagonists have been recently developed and their in vitro and in vivo properties are currently under investigation. The discovery of more potent and selective GPR55 inhibitors and their testing in tumour models will be instrumental to understand the significance of GPR55 inhibition in cancer and metastasis progression. A potential future field of investigation for GPR55 inhibitors is to test their activity on distinct subpopulations of cancer cells, such as the cancer stem cells, that are known to play a pivotal role in several types of cancer (Fitzgerald et al., 2015, McCubrey et al., 2014).