1372 Biochemical Society Transactions (2014) Volume 42, part 5 Lysophosphatidylinositol: a novel link between ABC transporters and G-protein-coupled receptors Emily L. Ruban*, Riccardo Ferro*, Syamsul Ahmad Arifin* and Marco Falasca* 1 *Inositide Signalling Group, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, 4 Newark Street, London E1 2AT, U.K. Abstract Lysophosphatidylinositol (LPI) is a well-known bioactive lipid that is able to activate signalling cascades relevant to cell proliferation, migration, survival and tumorigenesis. Our previous work suggested that LPI is involved in cancer progression since it can be released in the medium of Ras-transformed fibroblasts and can function as an autocrine modulator of cell growth. Different research groups have established that LPI is the specific and functional ligand for G-protein-coupled receptor 55 (GPR55) and that this GPR55–LPI axis is able to activate signalling cascades that are relevant for different cell functions. Work in our laboratory has recently unravelled an autocrine loop, by which LPI synthesized by cytosolic phospholipase A 2 (cPLA 2 ) is pumped out of the cell by ATP-binding cassette (ABC) transporter C1 (ABCC1)/multidrug resistance protein 1 (MRP1), initiating a signalling cascade downstream of GPR55. Our current work suggests that blockade of this pathway may represent a novel strategy to inhibit cancer cell proliferation. Introduction For over 20 years, the lipid lysophosphatidylinositol (LPI) has attracted attention for its potential to act as a signalling molecule. In particular, its role appears to be associated with cancer development as higher levels of LPI were found in hyperproliferative cancer cells compared with normal cells. In addition, LPI was identified as able to mediate cancer cell proliferation. Another strong link between LPI and cancer has recently been established with the identification of its receptor, G-protein-coupled receptor 55 (GPR55). Indeed, LPI through binding to GPR55 has been found to regulate the proliferation of different cancer cells [1]. Furthermore, in prostate and ovarian cancer cells, we have found that the enzyme cytosolic phospholipase A 2 (cPLA 2 ) synthesizes a pool of intracellular LPI that is released by the ATP-binding cassette (ABC) transporter ABCC1. Once in the extracellular media, LPI activates GPR55 and signalling cascades downstream of the receptor stimulating cell proliferation (Figure 1). Such milestone discoveries helped our understanding of how LPI regulates one of the main cancer trademarks that is cell proliferation. These findings have led to intense interest in developing inhibitors that selectively block this signalling loop, retaining therapeutic efficacy in the hope of gaining a greater therapeutic window. The present review summarizes the different players (LPI, Key words: ABC (ATP-binding cassette) transporter, cancer cell proliferation, G-protein-coupled receptor 55 (GPR55), lysophosphatidylinositol (LPI), phospholipase A2. Abbreviations: AA, arachidonic acid; ABC, ATP-binding cassette; CFTR, cystic fibrosis trans- membrane conductance regulator; CNS, central nervous system; cPLA2, cytosolic phospholipase A2; ERK, extracellular-signal-regulated kinase; GPCR, G-protein-coupled receptor; GPR55, G- protein-coupled receptor 55; HEK, human embryonic kidney; LPI, lysophosphatidylinositol; MDR, multidrug resistance; MRP1, multidrug-resistance protein 1; NBD, nucleotide-binding domain; PI, phosphoinositide; PLA, phospholipase A; SUR, sulfonylurea receptor; TMD, transmembrane domain. 1 To whom correspondence should be addressed (email m.falasca@qmul.ac.uk). ABC transporters and GPR55) of such feedback loops and analyses the development of viable therapeutic strategies relative to these druggable targets. Lysophosphatidylinositol LPI is a bioactive lipid that is composed of an inositol headgroup and a glycerol moiety linked to an acyl chain either in its sn-1 or in its sn-2 position (Figure 2). LPI is generated by the phospholipase A (PLA) family of lipases, which is believed to play an important role in several diseases [1]. The PLA family of lipases consists of the PLA 1 and PLA 2 subfamilies [2]. The designation of PLA 1 or PLA 2 relates to the target of the enzyme. PLA 1 enzymes catalyse hydrolysis of fatty acids from the sn-1 position of glycerophospholipids, generating 2-acyl- lysophospholipids and non-esterified (‘free’) fatty acids. PLA 2 enzymes catalyse hydrolysis at the sn-2 position of glycerophospholipids, releasing non-esterified fatty acids and 1-acyl-lysophospholipids (Figure 2). Alongside LPI, the eicosanoid and prostaglandin precursor arachidonic acid (AA) is also generated from phosphoinositide (PI) hydrolysis. For a long time, LPI was only considered as a secondary metabolic product of the AA pathway, before many studies uncovered its biological properties. It was first noticed that LPI could increase intracellular calcium in pancreatic cells, leading to an enhanced release of insulin [3,4]. Shortly after, another study also revealed that LPI was driving the vitamin D effect of increased intracellular calcium concentrations in hepatocytes [5]. Recently, LPI has also been linked to metabolic disorders such as obesity, as LPI plasma levels were reported to be higher in obese patients [6]. In this study, it was demonstrated that LPI not only stimulates lipogenic gene transduction, therefore inducing C  The Authors Journal compilation C  2014 Biochemical Society Biochem. Soc. Trans. (2014) 42, 1372–1377; doi:10.1042/BST20140151 Biochemical Society Transactions www.biochemsoctrans.org