Lysophosphatidic acid downregulates tissue inhibitor of metalloproteinases, which are negatively involved in lysophosphatidic acid-induced cell invasion

Abstract

Ovarian cancer is a highly metastatic disease. Lysophosphatidic acid (LPA) levels are elevated in ascites from ovarian cancer patients, but its potential role in ovarian cancer metastasis has just begun to be revealed. In this work, we show that LPA stimulates invasion of primary ovarian cancer cells, but not ovarian epithelial or borderline ovarian tumor cells, although these benign cells indeed respond to LPA in cell migration. We have found that LPA downregulates tissue inhibitor of metalloproteinases (TIMPs). TIMP2 and TIMP3 play functional role in LPA-induced invasion as negative regulators. G(i) protein, phosphatidylinositol-3 kinase (PI3K), p38 mitogen-activated protein kinase (MAPK), cytosolic phospholipase A(2) and urokinase type plasminogen activator (uPA) are required for LPA-induced cells invasion. TIMP3 may affect two independent downstream targets, vascular endothelial growth factor receptor and p38 MAPK. In vivo, LPA stimulates tumor metastasis in an orthotopic ovarian tumor model, which can be inhibited by a PI3K inhibitor, LY294002. In summary, LPA is likely a key component for promoting ovarian metastasis in vivo. LPA downregulates TIMP3, which may have targets other than metalloproteinases. Our in vivo metastasis mouse model is useful for studying the efficacy of therapeutic regimes of ovarian cancer.

Lysophosphatidic acid stimulates cell migration, invasion, and colony formation as well as tumorigenesis/metastasis of mouse ovarian cancer in immunocompetent mice

“…Whereas LPA 1 plays a very important role in migration of breast, pancreatic, and prostate cancer cells (25,26), our data suggest that LPA 2 and LPA 3 are more important in cell adhesion, migration, and invasion of EOC cells, which are consistent with reports showing that LPA 1 is involved in the negative growth regulation in ovarian cancer cells and that LPA 2 and LPA 3 , but not LPA 1 , expression is up-regulated in last-stage EOC (27). In addition, we have shown that either inhibitors and/or dominantnegative forms of G i protein, phosphatidylinositol 3-kinase, or cytosolic phospholipase A 2 (cPLA 2 ) completely or nearly completely block LPA-induced cell migration in human EOC cells, suggesting that these three molecules play a pivotal role in this process (2,10,11,24). The PLA 2 family of enzymes catalyzes the hydrolysis of the sn-2 position of phospholipids to generate free fatty acids (arachidonic acid in particular) and lysophosholipids.…”

“…Only recently, animal studies showing a role for LPA and/or its receptors in the development of cancers in vivo have been published (5)(6)(7)(8)(9). We have recently provided the first direct evidence that LPA stimulates tumor metastasis in vivo, which is inhibited by LY294002, a phosphatidylinositol 3-kinase inhibitor, and by 17-dimethylaminoethylamino-17-demethoxygeldanamycin, an inhibitor of the heat shock protein 90, which stabilizes hypoxia-inducible factor-1α (10,11). However, these experiments were conducted using nude or severe combined immunodeficient mice, which are immunocompromised.…”

“…We and others have shown that LPA stimulates the migration and invasion of ovarian cancer cells (10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22). Although most, if not all, of these studies were conducted in established ovarian cancer cell lines, we have recently conducted LPA-and S1P-induced cell migration and invasion experiments in primary EOC and nonmalignant human ovarian surface epithelial cells (11,23).…”

“…The PLA 2 family of enzymes catalyzes the hydrolysis of the sn-2 position of phospholipids to generate free fatty acids (arachidonic acid in particular) and lysophosholipids. We have recently shown that LPA regulates both cPLA 2 expression and activation (assessed by its phosphorylation) in human EOC cells (11,24). The role of cPLA 2 in cell migration is likely related to its ability to produce arachidonic acid (15,17,24).…”

Toward an Integrative Analysis of the Tumor Microenvironment in Ovarian Epithelial Carcinoma

“…TIMP1 is specific for MMP-9 inactivation, while TIMP2 inhibits MMP-2 and TIMP3 suppresses both MT1-MMP and MMP-9. Decreased levels of these three TIMPs have been associated with OEC through LPA-mediated interactions [91].…”