Abstract 5561: Dual targeting of angiotensin receptors (AGTR1 and AGTR2) as a new therapeutic strategy in epithelial ovarian carcinoma.
Authors: Park Young Ae , Lee Jeong-Won , Bae Duk-Soo , Kim Byoung-Gie , Kim Ha-Jeong , Choi Chel Hun 
Published: August 2014

Renin-Angiotensin system (RAS) is well known for its effect on the cardiovascular homeostasis by regulating arterial pressure. Accumulating evidences have been recently reported its paracrine regulation of tumorigenesis in several cancer types. Angiotensin type II receptor (AGTR) 1 and AGTR2 are the main effecter and known to act as antagonist to each other; AGTR1 plays as oncogene via positively regulating VEGF secretion, cell proliferation and conversely, AGTR2 does as tumor suppressor gene via decreasing not only angiogenesis but cell viability. Accumulating studies have revealed the correlation of these two receptors to the tumorigenesis through analysis of immunohistochemistry and in vitro data. Collectively, molecular targeting for them is being regarded as a novel strategy of cancer therapy. Treatment of either peptide antagonist of AGTR1, sartan or CGP-42112A, AGTR2 agonist has been shown to inhibit tumor progression in several cancer cells. In this study, we investigated the potentials of AGTR as therapeutic target in epithelial ovarian carcinoma. We estimated the expression of AGTR1 and AGTR2 in ovarian cancer cell lines and further tested whether modification of their activity could induce therapeutic effects. We performed MTT assay and ELISA for determining cell proliferation and secretion of VEGF, respectively. The expressions of AGTR1 or AGTR2 were variable but reciprocal among ovarian cancer cell lines. Stimulation of AGTR1 by treatment of angiotensin (Ang) II increased both cell proliferation and VEGF secretion of ovarian cancer cells expressing AGTR1. When the activity of AGTR1 was down-regulated by siRNA or specific antagonists, losartan or those of AGTR2 was up-regulated by plasmid or agonist CGP42112A, AngII mediated oncogenic effects were reduced. Inversing basal activity of AGTR1 and AGTR2 by treatment with losartan or CGP42112A synergistically enhanced decrease of both cell viability and secretion of VEGF in ovarian cancer cells. Moreover, combined treatment induced synergistic decrease of phosphorylation of PLCβ3 that is one of known downstream of AGTR1 and AGTR2, providing evidences that could explain the mechanism by which AGTR1 and AGTR2 could affect tumorigenesis in ovarian cancer cells. Interestingly, these enhancements were also reproduced in HUVEC (human umbilical vein endothelial cell) and by comparison, we found that both individual and combined treatment were more effective in endothelial cells in comparison to the ovarian cancer cells, implying the therapeutic effect of targeting AGTR in tumor microenvironment also. Taken together, these results suggested that dual targeting of AGTR 1 and 2 could be a possible therapeutic strategy in the treatment of epithelial ovarian cancer.

Citation Format: Young Ae Park, Jeong-Won Lee, Duk-Soo Bae, Byoung-Gie Kim, Ha-Jeong Kim, Chel Hun Choi. Dual targeting of angiotensin receptors (AGTR1 and AGTR2) as a new therapeutic strategy in epithelial ovarian carcinoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5561. doi:10.1158/1538-7445.AM2013-5561