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Role of Decreased Levels of Lipid Phosphate Phosphatase-1 in Accumulation of Lysophosphatidic Acid in Ovarian Cancer¹

Departments of Molecular Therapeutics [J. L. T., Y. H., R. L., K. W. C., G. B. M.], Gynecological Oncology [J. K. W., K. L.], Experimental Therapeutics [R. C. B., E. A. F., R. A. N.], Pathology [R. B.], and Biomathematics [E. N. A., J. M. Y.], University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030; Department of Cell and Developmental Biology [A. J. M.], University of North Carolina, Chapel Hill, North Carolina; Department of Obstetrics and Gynecology, [A. B.], Duke University Medical Center, Durham, North Carolina; Department of Laboratory Medicine and Pathology [D. I. S.], Endocrine Research Unit [K. K.], Mayo Foundation, Rochester, Minnesota; Department of Obstetrics, Gynecology and Reproductive Sciences and Cancer Research Institute [K. S-M.], University of California at San Francisco, San Francisco, California; and Department of Obstetrics and Gynecology, Northwestern University Hospital, Chicago, Illinois [D. F.]

ABSTRACT

The levels of lysophosphatidic acid (LPA) are consistently elevated in the ascites of ovarian cancer patients, suggesting that ovarian cancer cells are exposed to an LPA replete environment. LPA stimulates cell proliferation, cell survival, resistance to cisplatin, production and activation of proteases, invasiveness and production of the neovascularizing factors, vascular endothelial growth factor, and interleukin 8. Although ovarian cancer cells can produce LPA, this may not be the major reason for altered LPA levels in ascites. We have demonstrated that the major mechanism of degradation of LPA by ovarian cancer cells is through a lipid phosphate phosphatase (LPP)-like activity. We demonstrate herein that LPP-1 mRNA is decreased in the majority of ovarian cancers. This is recapitulated in ovarian cancer cell lines, where LPP-1 RNA levels are lower than those in normal ovarian epithelium and immortalized ovarian epithelial cells. Introduction of LPP-1 into ovarian cancer cell lines results in increased LPA hydrolysis, which is associated with a marked inhibition of cell proliferation and colony-forming activity and a marked increase in apoptosis. Thus, the LPA-rich environment of the ovarian cancer cell in vivo and the subsequent effects of cellular pathophysiology may be a consequence of both increased LPA production and decreased LPA metabolism by ovarian cancer cells.

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