A role for L‐α‐lysophosphatidylinositol and GPR55 in the modulation of migration, orientation and polarization of human breast cancer cells

Abstract

Background and purpose:Increased circulating levels of L-a-lysophosphatidylinositol (LPI) are associated with cancer and LPI is a potent, ligand for the G-protein-coupled receptor GPR55. Here we have assessed the modulation of breast cancer cell migration, orientation and polarization by LPI and GPR55. Experimental approach: Quantitative RT-PCR was used to measure GPR55 expression in breast cancer cell lines. Cell migration and invasion were measured using a Boyden chamber chemotaxis assay and Cultrex ® invasion assay, respectively. Cell polarization and orientation in response to the microenvironment were measured using slides containing nanometric grooves. Key results: GPR55 expression was detected in the highly metastatic MDA-MB-231 breast cancer cell line. In these cells, LPI stimulated binding of [ 35 S]GTPgS to cell membranes (pEC50 6.47 Ϯ 0.45) and significantly enhanced cell chemotaxis towards serum. MCF-7 cells expressed low levels of GPR55 and did not migrate or invade towards serum factors. When GPR55 was over-expressed in MCF-7 cells, serum induced a robust migratory and invasive response, which was further enhanced by LPI and prevented by siRNA to GPR55. The physical microenvironment has been identified as a key factor in determining breast tumour cell metastatic fate. LPI endowed MDA-MB-231 cells with the capacity to detect shallow (40 nm deep) grooved slides and induced marked cancer cell polarization on both flat and grooved surfaces. Conclusions and implications: LPI and GPR55 play a role in the modulation of migration, orientation and polarization of breast cancer cells in response to the tumour microenvironment.

The orphan G protein-coupled receptor GPR55 promotes cancer cell proliferation via ERK

“…It is therefore tempting to speculate that LPI, through GPR55, would behave similar to their close relatives lysophosphatidic acid and sphingosine-1-phosphate in terms of involvement in cancer biology. A very recent work proposed that LPI induces MCF-7 cell migration in a GPR55-mediated manner (Ford et al, 2010). It has also been described that cytosolic phospholipase A2 generates mitogenic LPI in Ras-transformed epithelial cells (Falasca and Corda, 1994) and Ras-transformed fibroblasts (Falasca et al, 1998).…”

International Union of Basic and Clinical Pharmacology. LXXXVIII. G Protein-Coupled Receptor List: Recommendations for New Pairings with Cognate Ligands

“…4028) as an endogenous agonist (Oka et al, 2007). The activation of GPR55 by LPI has been described by numerous groups (Lauckner et al, 2008;Waldeck-Weiermair et al, 2008;Henstridge et al, 2009Henstridge et al, , 2010Kapur et al, 2009;Whyte et al, 2009;Yin et al, 2009;Bondarenko et al, 2010;Ford et al, 2010;Oka et al, 2010a;Ishiguro et al, 2011;Pineiro et al, 2011;Southern et al, 2013). Commercially available LPI is primarily plant-derived, containing mixtures of fatty acid substituents with a majority of mediumchain saturated and monounsaturated fatty acids at the 1-position of LPI (Oka et al, 2009).…”

A Selective Antagonist Reveals a Potential Role of G Protein–Coupled Receptor 55 in Platelet and Endothelial Cell Function

“…GPR55 is highly abundant in the central nervous system as well as in intestine, bone marrow, spleen, platelets, and immune and endothelial cells (Sawzdargo et al, 1999;Ryberg et al, 2007;Waldeck-Weiermair et al, 2008;Pietr et al, 2009;Balenga et al, 2011a;Henstridge et al, 2011;Rowley et al, 2011). Moreover, GPR55 has been detected in a variety of cancer tissues and cancer cell lines (Ford et al, 2010;Andradas et al, 2011;Huang et al, 2011;Pineiro et al, 2011;Perez-Gomez et al, 2012). Several endogenous GPR55 signaling pathways have been described to date despite controversial findings concerning its agonists and antagonists (Balenga et al, 2011b).…”