Abstract 158: Sustained Adrenergic Signaling Activates Pro-Inflammatory Networks in Ovarian Carcinoma

Abstract Purpose: To determine the role of adrenergic activation in driving tumor inflammation through COX-2/Prostaglandin E2 (PGE2) axis as PGE2 is known to play an important role in the induction of a pro-inflammatory signature in the tumor microenvironment that promotes tumor growth and metastasis. Methods We first analyzed global metabolic changes in tumors isolated from patients with known Center for Epidemiologic Studies Depression Scale (CES-D; depressive) scores and tumoral norepinephrine (NE) levels. Beta-adrenergic receptor (ADRB) positive cells (Skov3 and HeyA8) were used to study mechanism at gene and protein levels of PTGS2 (cyclooxygenase2), PTGES (prostaglandin E synthase) and metabolite levels (all prostaglandins, PGs) in vitro and in vivo. Results Our results revealed that levels of PGs were significantly increased in patients with high CESD scores (>16). PGE2 was upregulated by 2.38 fold when compared to the low CES-D scores. A similar trend was also observed with other pro-inflammatory eicosanoids, such as 6-keto prostaglandin F1 Alpha (2.03), prostaglandin A2 (1.39) and prostaglandin E1 (1.39). Exposure to NE resulted in increased PTGS2 and PTGES (prostaglandin E2 synthase) gene expression in adrenergic receptor positive cell lines. Mass-spectroscopy analyses confirmed that upon treatment with NE and arachidonic acid (substrate), PGE2 levels were increased in conditioned medium from Skov3 cells. Treatment with a broad ADRB agonist (isoproterenol) or ADRB2 specific agonist (terbutaline) led to increases in expression of PTGS2 and PTGES. Conversely, treatment with a broad antagonist (propranolol) or an ADRB2 specific antagonist (butoxamine) in the presence of NE abrogated gene expression changes of PTGS2 and PTGES. Silencing PTGS2 resulted in significantly decreased migration (40%) and invasion (25%) of Skov3 and HeyA8 cells in the presence of NE. Importantly, silencing PTGS2 in a restraint stress orthotropic model decreased tumor burden by 70% and metastasis (tumor confined to the ovary) in Skov3-ip1 orthotopic mouse model as compared to control siRNA with restraint stress. Conclusion Increased adrenergic stimulation results in a pro-inflammatory milieu that drives tumor progression and metastasis. Citation Format: Archana S. Nagaraja, Guillermo Armaiz-Pena, Julie Allen, Nouara C. Sadaoui, Behrouz Zand, Peiying Yang, Lin Tan, Steve Cole, Susan Lutgendorf, Anil K. Sood. Sustained adrenergic signaling activates pro-inflammatory networks in ovarian carcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 158. doi:10.1158/1538-7445.AM2014-158