Lysophosphatidic Acid Signaling in Ovarian Cancer

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DESCRIPTION (provided by applicant): The overall goal of this proposal is to study the regulation of signaling pathways mediated by lysophosphatidic acid (LPA) and its associated receptors in ovarian cancer cells. LPA acid and its associated receptors, EDG2, EDG4 and EDG7 of the endothelial differentiation gene (EDG) family, have been shown to contribute to ovarian cancer cell proliferation and tumor invasion. Overexpression of EDG4 has been implicated in the progression of ovarian cancer. Thus, these LPA receptors could serve as therapeutic targets in ovarian cancer. In this proposal, we provided the first evidence for the regulation of EDG4 functions by the proapoptotic protein, Siva-1, and the focal adhesion molecule, TRIP6 (Thyroid Receptor Interacting Protein 6). Our long-term goal is to design nove strategies specifically targeting LPA receptors for therapeutic treatment. Three specific aims will be addressed. In Aim 1, a role for Siva-1 in down-regulation of LPA signaling and induction of apoptosis will be determined. Biochemical approaches and yeast genetics wiIl be utilized to determine the functional significance of the interaction between Siva-1 and EDG4. In Aim 2, the role of TRIP6 in LPA-dependent, EDG4-mediated cell migration and mitogenic signaling will be explored by biochemical approaches and immunofluorescence microscopy. In Aim 3, the specificity of Siva-1 and TRIP6 in regulating different LPA receptors will be determined by biochemical approaches. The knowledge obtained from this study will gain insight into the understanding of LPA signaling and regulation in ovarian cancer.