© 2003 by Oxford University Press
Journal of the National Cancer Institute, Vol. 95, No. 10, 733-740,
May 21, 2003
© 2003 Oxford University Press
ARTICLE |
Dual Mechanisms for Lysophosphatidic Acid Stimulation of Human Ovarian Carcinoma Cells
Affiliations of authors: Y.-L. Hu, R. B. Jaffe, Center for Reproductive Sciences, University of California, San Francisco; C. Albanese, R. G. Pestell, Division of Hormone Dependent Tumor Biology, Albert Einstein College of Medicine, Bronx, NY.
Correspondence to: Robert B. Jaffe, M.D., Center for Reproductive Sciences, HSW 1695, University of California, San Francisco, 505 Parnassus Ave., San Francisco, CA 94143–0556 (e-mail: jaffer{at}obgyn.ucsf.edu).
Background: Lysophosphatidic acid (LPA), at concentrations present in ascitic fluid, indirectly stimulates the growth of malignant ovarian tumors by increasing the expression of vascular endothelial growth factor (VEGF) in ovarian cancer cells. We investigated whether LPA could also directly promote ovarian tumor growth by increasing the level of cyclin D1, a key G1-phase checkpoint regulator, which thereby increases cell proliferation. Methods: Expression of cyclin D1 and LPA receptors (EDG4 and EDG7) was determined in six ovarian cancer cell lines (including OVCAR-3 cells) and immortalized ovarian surface epithelial cells (IOSE-29). Cyclin D1 promoter activity was measured in LPA-treated OVCAR-3 cells cotransfected with cyclin D1 promoter-driven luciferase constructs and cDNA expression plasmids for I
B
M (a nuclear factor B [NFB] super-repressor). Results: Four of six cancer cell lines, including OVCAR-3, overexpressed cyclin D1 protein relative to levels in IOSE-29 cells. LPA treatment increased cyclin D1 protein in a dose- and time-dependent manner in OVCAR-3 cells but not in IOSE-29 cells. LPA stimulated cyclin D1 promoter activity (3.0-fold, 95% confidence interval [CI] = 2.7-fold to 3.3-fold). Mutation of the NFB-binding site in the cyclin D1 promoter to block NFB binding and expression of IBM, which binds NFB and inhibits its binding to the promoter, markedly diminished LPA stimulation of cyclin D1 promoter activity (activity stimulated only 1.4-fold, 95% CI = 1.1-fold to 1.7-fold, and 0.7-fold, 95% CI = 0.6-fold to 0.8-fold, respectively). EDG4 was overexpressed in all cancer cell lines studied relative to that in IOSE-29 cells, but EDG7 was overexpressed in only two lines. Conclusions: Dual mechanisms are probably involved in LPA stimulation of ovarian tumor growth in vivo. In addition to the previously characterized indirect mechanism that increases angiogenesis via VEGF, LPA may directly increase the level of cyclin D1 in ovarian cancer cells, increasing their proliferation.
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