lysophosphatidylinositol and Neoplasms

Topics: Carcinogenesis; Cell Proliferation; Humans; Lysophospholipids; Neoplasms; Receptors, Cannabinoid; Receptors, G-Protein-Coupled; Signal Transduction

Lysophosphatidylinositol (LPI) is a bioactive lipid generated by phospholipase A2 which is believed to play an important role in several diseases. Indeed LPI can affect various functions such as cell growth, differentiation and motility, in a number of cell-types, including cancer cells, endothelial cells and nervous cells. Despite the fact that LPI-induced cellular functions had been known for more than twenty years, the recent discovery that in several cell-types the orphan G protein-coupled receptor GPR55 acts as the specific receptor for LPI has fuelled novel interest in this lysolipid. Different research groups, including our own, have recently suggested that LPI may be the specific and functional ligand for GPR55, triggering signalling cascades that are relevant to cell proliferation, migration, survival and tumourigenesis. Recently published data suggest that the LPI/GPR55 axis plays an important role in different physiological and pathological contexts. Here we review the available data supporting the role of LPI in cell signalling and the pharmacology of its putative receptor GPR55.

Topics: Animals; Cell Differentiation; Cell Movement; Cell Proliferation; Humans; Lysophospholipids; Models, Biological; Neoplasms; Receptors, Cannabinoid; Receptors, G-Protein-Coupled; Signal Transduction

G protein-coupled receptor 55 (GPR55) is a recently deorphanized lipid- and peptide-sensing receptor. Its lipidic endogenous agonists belong to lysoglycerophospholipids, with lysophosphatidylinositol (LPI) being the most studied. Peptide agonists derive from fragmentation of pituitary adenylate cyclase-activating polypeptide (PACAP). Although GPR55 and its ligands were implicated in several physiological and pathological conditions, their biological function remains unclear. Thus, the aim of the study was to conduct a large-scale re-analysis of publicly available gene expression datasets to identify physiological and pathological conditions affecting the expression of GPR55 and the production of its ligands. The study revealed that regulation of GPR55 occurs predominantly in the context of immune activation pointing towards the role of the receptor in response to pathogens and in immune cell lineage determination. Additionally, it was revealed that there is almost no overlap between the experimental conditions affecting the expression of GPR55 and those modulating agonist production. The capacity to synthesize LPI was enhanced in various types of tumors, indicating that cancer cells can hijack the motility-related activity of GPR55 to increase aggressiveness. Conditions favoring accumulation of PACAP-derived peptides were different than those for LPI and were mainly related to differentiation. This indicates a different function of the two agonist classes and possibly the existence of a signaling bias.

Topics: Cell Differentiation; Data Mining; Databases, Nucleic Acid; Gene Expression Regulation, Neoplastic; Humans; Lysophospholipids; Neoplasm Proteins; Neoplasms; Pituitary Adenylate Cyclase-Activating Polypeptide; Receptors, Cannabinoid

Evidence points to a role of L-α-lysophosphatidylinositol (LPI) in cancer. First, clinical data identified LPI as a biomarker for poor prognosis in cancer patients. Second, in vitro studies demonstrated significantly elevated levels of LPI in highly proliferative cancer cells. Third, LPI displays mitogenic activity in cancer cell lines, in which the lipid significantly increased cell proliferation. However, a receptor target for LPI remained elusive until very recently. It has now been revealed that LPI activates GPR55, a G protein-coupled receptor that couples to G(12/13) and G(q) proteins, which direct oncogenic signalling. New evidence indicates that LPI and GPR55 are key partners in driving cancer cell proliferation and migration. GPR55 is expressed in human tumours and drives proliferation and its expression correlates with tumour aggressiveness. Overall patient survival is lower in patients whose glioblastomas express higher levels of GPR55. Thus, evidence suggests that interaction with GPR55 might underlie the pro-tumoural actions of LPI.

Topics: Animals; Biomarkers, Tumor; Cell Movement; Cell Proliferation; Glioblastoma; Humans; Lysophospholipids; Neoplasms; Receptors, Cannabinoid; Receptors, G-Protein-Coupled; Survival