LYSOPHOSPHATIDIC ACID IS A MEDIATOR OF INTERLEUKIN-6 PRODUCTION IN OVARIAN CANCER CELLS

Lysophosphatidic acid (LPA) is a naturally occurring bioactive lysophospholipid that mediates a broad range of cellular processes such as cell proliferation, survival, migration and invasion. LPA also plays a potential role in human oncogenesis as suggested by elevated expression of its receptors and its producing enzymes in malignant tissues. In the current study, we demonstrated that LPA is a potent mediator of interleukin-6 (IL-6) production in ovarian cancer. IL-6 is a pleiotropic cytokine which is thought to be an important mediator of ovarian cancer development and progression. Here, we demonstrated that IL-6 levels are indeed increased in the plasma of ovarian cancer patients as compared to normal women. The IL-6 concentrations in ascites of ovarian cancer patients are even higher than those present in the plasma samples. These results suggest that increased IL-6 are expressed and secreted by ovarian cancer cells, forming a gradient from the ascites to the blood. Ovarian cancer cells indeed produce IL-6 in culture. However, when these cells are starved in serum-free medium, they cease producing IL-6, suggesting that IL-6 is not constitutively expressed, but rather in response to exogenous factors present in serum. We showed that IL-6 expression is not driven by peptide growth factors such as insulin-like growth factor I or epidermal growth factor. Instead, IL-6 expression is most potently induced by the lysophospholipid growth factor LPA. Treatment of ovarian cancer cells with LPA leads to transcriptional activation of the IL-6 gene promoter through activation of the NF-kB and C/EBP transcription factors. LPA also induces tyrosine phosphorylation and activation of Stat-3, a well known intracellular effector of IL-6. However, blockade of IL-6 with a neutralizing antibody only slightly reduced Stat-3 phosphorylation in response to LPA, suggesting that LPA may induce Stat-3 directly or through secondary mediators other than IL-6. Together, these studies demonstrate the role of LPA in regulation of IL-6 production and the underlying mechanism in ovarian cancer