The mortality of most cancer patients is not due to their primary tumors, but rather from associated secondary metastasis. Chemotherapy is commonly used for the treatment of cancer. However, development of chemoresistance is one of the main reasons for treatment failure. Two bioactive lipid signaling molecules, lysophosphatidic acid (LPA) and sphingosine-l-phosphate (S1P) modulate cellular effects in different cancer cells, including ovarian cancer cells. We have recently shown that LPA and S1P stimulate phosphatidylinositol-3 kinase (PI3K)/Akt activation in ovarian cancer cells through a novel MAP kinase kinase (MEK)/extracellular mitogen-regulated kinase(ERK)-dependent signaling pathway. LPA and S1P stimulate cell migration (one of the most important processes in tumor cell metastasis) and inhibit the caspase-3 activity induced by paclitaxel (increase chemoresistance). Both G_/o and PI3K are involved in these processes. Our overall objective of this proposal is to understand the signaling mechanisms controlling growth, cell survival, and migration in ovarian cancer cells. We propose that MAP kinase and PI3K/Akt! signaling pathways interact with each other and that MEK/ERK is a common target for both growth stimulation and anti-apoptotic effects induced by LPA and S1P in ovarian cancer cells. We hypothesize an autocrine LPA loop that is involved in cell migration induced by laminin and a PI3K/MEK switch model that controls cell proliferation/survival and migration. Furthermore, we propose that p38 MAP kinase is differentially activated by varied stimuli in different cell lines. These hypotheses will be tested in three Specific Aims.
Specific Aim 1. Investigate the hypothesis that ERK mediates both growth-promoting and anti-apoptotic effects of LPA and SIP in ovarian cancer cells. Both pharmacological and genetic approaches will be used in these studies.
Specific Aim 2. Investigate the mechanisms of laminin-induced LPA production and LPA-induced cell migration and chemoresistance. We will test both the LPA autocrine loop and the PI3K switch models in this aim.
Specific Aim 3. Determine the mechanisms of stimulus- and cell line-specificity of MEKIERK-dependent p38/Akt activation. LPA and S1P induce MEK/ERK-dependent p38/Akt activation in a cell line- and stimulus-specific manner. We will investigate the mechanisms of these specificities. The proposed studies are highly relevant to cancer, particularly ovarian cancer. The LPA autocrine loop and the PI3K switch models are novel. Our studies will provide important information on the effectiveness of targeting PI3K and/or ERK on blocking cell proliferation, survival, and migration. The long-term goal of these studies is to identify novel targets to be used as potential therapeutics for the treatment of cancer.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Pathology B Study Section (PTHB)
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Sathyamoorthy, Neeraja
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Indiana University-Purdue University at Indianapolis
Internal Medicine/Medicine
Schools of Medicine
United States
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Funke, Manuela; Zhao, Zhenwen; Xu, Yan et al. (2012) The lysophosphatidic acid receptor LPA1 promotes epithelial cell apoptosis after lung injury. Am J Respir Cell Mol Biol 46:355-64
Cai, Qingchun; Zhao, Zhenwen; Antalis, Caryl et al. (2012) Elevated and secreted phospholipase A? activities as new potential therapeutic targets in human epithelial ovarian cancer. FASEB J 26:3306-20
Li, Hui; Zhao, Zhenwen; Antalis, Caryl et al. (2011) Combination therapy of an inhibitor of group VIA phospholipase A2 with paclitaxel is highly effective in blocking ovarian cancer development. Am J Pathol 179:452-61
Li, Hui; Zhang, Hong; Wei, Gang et al. (2011) Tumor cell group via phospholipase Aýýý is involved in prostate cancer development. Prostate 71:373-84
Li, Hui; Zhao, Zhenwen; Wei, Gang et al. (2010) Group VIA phospholipase A2 in both host and tumor cells is involved in ovarian cancer development. FASEB J 24:4103-16
Zhao, Zhenwen; Xu, Yan (2010) An extremely simple method for extraction of lysophospholipids and phospholipids from blood samples. J Lipid Res 51:652-9
Zhao, Zhenwen; Xu, Yan (2009) Measurement of endogenous lysophosphatidic acid by ESI-MS/MS in plasma samples requires pre-separation of lysophosphatidylcholine. J Chromatogr B Analyt Technol Biomed Life Sci 877:3739-42
Li, Hui; Wang, Dongmei; Zhang, Hong et al. (2009) Lysophosphatidic acid stimulates cell migration, invasion, and colony formation as well as tumorigenesis/metastasis of mouse ovarian cancer in immunocompetent mice. Mol Cancer Ther 8:1692-701
Wang, Dongmei; Zhao, Zhenwen; Caperell-Grant, Andrea et al. (2008) S1P differentially regulates migration of human ovarian cancer and human ovarian surface epithelial cells. Mol Cancer Ther 7:1993-2002
Tager, Andrew M; LaCamera, Peter; Shea, Barry S et al. (2008) The lysophosphatidic acid receptor LPA1 links pulmonary fibrosis to lung injury by mediating fibroblast recruitment and vascular leak. Nat Med 14:45-54

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