Lysophospholipid Mediators in Ovarian Cancer

描述(申请人提供)：癌细胞的增殖由 正常细胞通路的过度表达或突变激活 控制细胞的生长和分化。最近的研究表明，自分泌 受体导向的脂生长因子溶血磷脂ADID的作用 (LPA)在卵巢癌的病因学中起核心作用。增长， 卵巢癌细胞的侵袭性和对化疗药物的耐药性 都依赖于LPA。卵巢癌细胞合成LPA并释放 中介物进入腹水，积聚在腹膜并洗澡 腹部肿瘤。目前治疗晚期卵巢癌的方法包括 手术、放疗和化疗并没有提高癌症的治愈率 疾病。因此，靶向LPA的合成和作用可以提供一种 卵巢癌药物干预的新治疗策略。 尽管参与LPA反应的受体和信号通路是 令人惊讶的是，人们对这些酶和细胞 参与LPA合成、释放和失活的过程。我们有 已确定的磷脂酶和脂磷酸酶在 LPA及相关生物活性脂质介体的合成与代谢。这个 本提案中描述的研究的目标是定义酶和 卵巢癌合成和失活LPA的途径 细胞。这些途径的分子遗传学和药理学操作 将使我们能够评估针对LPA的治疗的可能性 卵巢癌治疗中的代谢问题。圆满完成 研究将为开发新的有效的产品提供框架和动力 卵巢癌的治疗。

DESCRIPTION (provided by applicant): 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.