Creating a Dead End for Cancer: The Role of LPA Receptors 1/3 and 2 in Ovarian Cancer

Abstract—Lysophosphatidic Acid (LPA), a natural phospholipid, has been implicated as a signaling molecule of migration in invasive malignancies like ovarian cancer. The migration of ovarian cancer is a process that is poorly understood. This study investigated the role of LPA Receptors 1/3 and 2 in the migratory response and protein signaling pathways of ovarian cancer cells (OVCAR) by using a LPA Receptor 1/3 antagonist (Ki16425) and a LPA Receptor 2 agonist (dodecylphosphate). Using a modified Boyden migration assay, it was determined that OVCAR cells migrate in a dose response fashion towards LPA compared to untreated control (p<0.05). It was also determined that the LPA Receptor 1/3 antagonist inhibited migration toward LPA in a dose response fashion compared to untreated control (P<0.05). LPA Receptor 2 agonist inhibited migration towards LPA; combined treatment of LPA Receptor 1/3 antagonist and LPA Receptor 2 agonist inhibited 95 percent of OVCAR migration (p<0.05). Vascular Endothelial Growth Factor (VEGF), an angiogenesis regulator, Epidermal Growth Factor Receptor (EGFR), a known migration regulator, and RhoA, a suggested cell cytoskeleton activator, were investigated to determine the effect of LPA Receptors 1/3 and LPA Receptors 2 on protein quantities. Exogenous LPA up-regulated VEGF secretion and had no effect on RhoA activation or production of EGFR. LPA Receptors 1/3 were shown to inhibit VEGF secretion, stimulate RhoA activation, and have no effect on production of EGFR (p<0.05). LPA Receptor 2 was shown to stimulate VEGF secretion and RhoA activation. In summary, it was determined that LPA Receptors 1/3 are pro-migration, and LPA Receptor 2 is anti-migration- perturbing both receptors simultaneously resulted in a 95 percent reduction i