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, Gordon B. Mills

    Research output: Contribution to journalArticlepeer-review

    149 Scopus citations

    Abstract

    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-κB and AP-1, two transcription factors that were strongly activated by LPA in ovarian cancer cell lines. Positive regulators of the NF-κB 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 LPA 3 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.

    Original languageEnglish (US)
    Pages (from-to)9653-9661
    Number of pages9
    JournalJournal of Biological Chemistry
    Volume279
    Issue number10
    DOIs
    StatePublished - Mar 5 2004

    ASJC Scopus subject areas

    • Biochemistry
    • Molecular Biology
    • Cell Biology

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