A novel laminin-induced LPA autocrine loop in the migration of ovarian cancer cells.
We have reported previously that levels of lysophosphatidic acid (LPA) are elevated in the blood and ascites from patients with ovarian cancer. LPA stimulates proliferation of ovarian cancer cells and has been proposed as an autocrine growth factor. Here, we show that a novel autocrine loop of LPA promotes the migration of ovarian cancer cells, which is a critical step of tumor metastasis. We report that laminin, but not other extracellular matrix proteins, induces LPA production in ovarian cancer cells. A neutralizing antibody against beta1 integrin and a calcium-independent phospholipase A2-specific inhibitor, HELSS, block both LPA production and the haptotactic activity of laminin. Exogenously added LPA restores the migratory ability of HEY ovarian cancer cells to laminin. These data suggest that laminin-induced cell migration is mediated by LPA. We further show that a specific receptor for LPA, LPA3, is required for mediating the chemotactic activity of LPA. In addition, we show that cytosolic PLA2 is required for cell migration and its activation is phosphatidylinositol-3 kinase-dependent. These findings have revealed a new mechanism of crosstalk between a beta1 integrin receptor and a G protein-coupled receptor.
Sengupta
Saubhik
S
Department of Cancer Biology, Lerner Research Institute, The Cleveland Clinic Foundation, 9500 Euclid Ave., Cleveland, Ohio 44195, USA.
Xiao
Yi-Jin
YJ
Xu
Yan
Y
D019898:Autocrine Communication; D002465:Cell Movement / Q000187:drug effects; D016326:Extracellular Matrix Proteins / Q000494:pharmacology; D005260:Female; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000502:physiology; D054522:Group VI Phospholipases A2; D006801:Humans; D019012:Integrin beta1 / Q000502:physiology; D007797:Laminin / Q000494:pharmacology*; D008246:Lysophospholipids / Q000096:biosynthesis* / Q000494:pharmacology; D008954:Models, Biological; D010051:Ovarian Neoplasms / Q000378:metabolism / Q000503:physiopathology*; D037342:Pertussis Toxin / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D010741:Phospholipases A / Q000502:physiology; D054467:Phospholipases A2; D014407:Tumor Cells, Cultured
D016326:Extracellular Matrix Proteins; D019012:Integrin beta1; D007797:Laminin; D008246:Lysophospholipids; D037342:Pertussis Toxin; D019869:Phosphatidylinositol 3-Kinases; D010741:Phospholipases A; D054522:Group VI Phospholipases A2; C516475:PLA2G6 protein, human; D054467:Phospholipases A2; D019206:GTP-Binding Protein alpha Subunits, Gi-Go