Abstract 5169: Functional studies of the prostaglandin E2 receptor EP4 in ovarian cancer

Ovarian cancer is the leading cause of death from gynecologic malignancy in the United States. Most cases of ovarian cancer present in late stages leading to recurrent disease which is incurable. Few effective targeted therapies are available to treat ovarian cancer other than non-specific, toxic chemotherapy. Ovarian cancer is often fatal due to innate or acquired chemoresistance. Lipid mediators are linked to many pathological processes including inflammation and cancer. The lipid prostaglandin E2 (PGE2) is synthesized by cyclooxygenases, COX-1 and COX-2, and elevated expression of COX and increased PGE2 levels are functionally linked to the progression of many cancers. PGE2 is exported from the cell where it acts in a paracrine and autocrine manner by activating a family of four G-protein coupled receptors (EP1-4) which are linked to different intracellular signaling pathways. EP1 is coupled to calcium mobilization and PKC; whereas, EP2 and EP4 activate PKA/cAMP, PI3K and ERK pathways. EP3 generally inhibits cAMP levels. COX-1 has been shown to be overexpressed in primary ovarian cancer as well as in many ovarian cancer cell lines. The EP4 receptor is overexpressed and plays a mechanistic role in various malignancies including breast and colon. Due to toxicity concerns surrounding global inhibition of the COX enzymes and, in an effort to identify new targeted therapies for the treatment of ovarian cancer, our objective was to determine the expression as well as the functional role of the PGE2 receptor EP4 in ovarian cancer. We hypothesized that the EP4 receptor is overexpressed in ovarian cancer and that binding of its cognate ligand, PGE2, will drive ovarian cancer progression and that inhibition of the EP4-mediated signaling will lead to inhibition of ovarian cancer growth and metastasis. In order to test these hypotheses, we analyzed the expression of the EP4 receptor in a human ovarian cancer tissue microarray (TMA) as well as human ovarian cancer cell lines. Immunohistochemical analysis of EP4 on the TMA composed of varying histologies, including serous, endometrioid and clear cell, as well as normal ovarian tissue revealed that EP4 was expressed in 38.7% of ovarian cancer patients; whereas, EP4 was not expressed in the 10 normal ovarian tissue samples. Additionally, in comparison to immortalized human ovarian surface epithelial (HOSE) cells, EP4 is overexpressed in many of the cell lines analyzed, including ES-2, OVCAR-3, COAV-3, SKOV3, OVISE and Kuramochi cells. Treatment of these cell lines with an EP4 antagonist resulted in decreased proliferation and migration compared to vehicle control. Consistent with the pharmacological data, treatment of ovarian cancer cell lines with siRNA directed against the EP4 receptor lead to decreased proliferation and migration. Based on these data, targeting of the PGE2 EP4 receptor should be investigated further for the treatment of ovarian cancer. Citation Format: Joceyln C. Reader, Paul Staats, Olga Goloubeva, Ningbo Jian, Dana M. Roque, Maya E. Matheny, Amy M. Fulton, Gautam G. Rao. Functional studies of the prostaglandin E2 receptor EP4 in ovarian cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5169.