Cancer cell proliferation is driven by overexpression or mutational activation of normal cellular pathways that control cell growth and differentiation. Recent work suggests that autocrine actions of the receptor-directed lipid growth factor lysophosphatidic adid (LPA) play a central role in the etiology of ovarian cancer. Growth, invasiveness and resistance to chemotherapeutics of ovarian cancer cells are all dependent on LPA. Ovarian cancer cells synthesize LPA and release this mediator into ascites fluid which accumulates in the peritoneum and bathes abdominal tumors. Current therapies for late stage ovarian cancer that include surgery, radiation and chemotherapy have not improved cure rates for the disease. Targeting the synthesis and actions of LPA may therefore provide a novel treatment strategy for pharmacological intervention in ovarian cancer. Although the receptors and signaling pathways involved in responses to LPA are well understood surprisingly little is known about the enzymes and cellular processes involved in LPA synthesis, release and inactivation. We have identified phospholipases and lipid phosphatases that play critical roles in the synthesis and metabolism of LPA and related bioactive lipid mediators. The goal of the research described in this proposal is to define the enzymes and pathways involved in the synthesis and inactivation of LPA by ovarian cancer cells. Molecular genetic and pharmacological manipulation of these pathways will allow us to evaluate the potential for therapies that target LPA metabolism in treatment of ovarian cancer. Successful completion of the research will provide the framework and impetus to develop novel effective therapeutics for ovarian cancer.
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