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J. Biol. Chem., Vol. 279, Issue 10, 9653-9661, March 5, 2004

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Mechanisms for Lysophosphatidic Acid-induced Cytokine Production in Ovarian Cancer Cells^*

Xianjun Fang, Shuangxing Yu, Robert C. Bast¶, Shuying Liu, Hong-Ji Xu, Shi-Xue Hu, Ruth LaPushin, Francois X. Claret, Bharat B. Aggarwal||, Yiling Lu, and Gordon B. Mills

From the Departments of Molecular Therapeutics, ^¶Experimental Therapeutics, and ^||Bioimmunotherapy, M. D. Anderson Cancer Center, Houston, Texas 77030

A potential role for lysophosphatidic acid (LPA) in human oncogenesis was first suggested by the observation that LPA is present at elevated levels in ascites of ovarian cancer patients. In the current study, we demonstrated that LPA is a potent inducer of interleukin-6 (IL-6) and interleukin-8 (IL-8) production in ovarian cancer cells. Both IL-6 and IL-8 have been implicated in ovarian cancer progression. We characterized the IL-8 gene promoter to ascertain the transcriptional mechanism underlying LPA -induced expression of these cytokines. LPA stimulated the transcriptional activity of the IL-8 gene with little effect on IL-8 mRNA stability. The optimal response of the IL-8 gene promoter to LPA relied on binding sites for NF-B and AP-1, two transcription factors that were strongly activated by LPA in ovarian cancer cell lines. Positive regulators of the NF-B and AP-1 pathways synergistically activated the IL-8 gene promoter. Further, the effect of LPA on IL-6 and IL-8 generation is mediated by the Edg LPA receptors as enforced expression of LPA receptors restored LPA-induced IL-6 and IL-8 production in non-responsive cells and enhanced the sensitivity to LPA in responsive cell lines. The LPA₂ receptor was identified to be the most efficient in linking LPA to IL-6 and IL-8 production although LPA₁ and LPA₃ were also capable of increasing the response to a certain degree. These studies elucidate the transcriptional mechanism and the Edg LPA receptors involved in LPA-induced IL-6 and IL-8 production and suggest potential strategies to restrain the expression of these cytokines in ovarian cancer.

Received for publication, June 23, 2003 , and in revised form, December 8, 2003.

^* The work was supported by the Lynne Cohen Foundation Ovarian Cancer Research Grant 80095031 (to X. F.), by National Institutes of Health Grants CA82716 and CA64602 (to G. B. M.), and by National Institutes of Health Core Grant 5P30 CA016672 (to M. D. Anderson Cancer Center). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Dept. of Biochemistry, Sanger Hall 2-006, Medical College of Virginia, Virginia Commonwealth University, 1101 East Marshall St., Richmond, VA 23298. Tel.: 804-828-0787; Fax: 804-828-1473; E-mail: xfang{at}vcu.edu.

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