title: Dual targeting of angiotensin receptors (AGTR1 and AGTR2) in epithelial ovarian carcinoma.
abstract: OBJECTIVE
  The renin-angiotensin system (RAS) influences cardiovascular homeostasis, and Angiotensin II type 1 receptor (AGTR1) is the main effector of RAS, and AGTR2 antagonizes AGTR1. Accumulating evidence supports the role of RAS in the paracrine regulation of tumorigenesis in several cancer types. Although treatment with AGTR1 antagonist (losartan) or AGTR2 agonist (CGP42112A) inhibits tumor progression in several cancer cells, their combined treatment has not been reported.
  
  
  METHODS
  In this study, we estimated the expression of AGTR1 and AGTR2 in epithelial ovarian cancer cells and tissues. Then, we evaluated the anti-cancer effects of combined treatment with losartan and/or CGP42112A in ovarian cancer cells and human umbilical vein endothelial cells (HUVEC).
  
  
  RESULTS
  AGTR1 protein was detected in 86% of ovarian cancer tissues, while AGTR2 was not detected in immunohistochemistry. The mRNA expression of AGTR1 obtained from the cancer genome atlas (TCGA) dataset showed that AGTR1 overexpression was correlated with poor survival. Treatment with either losartan or CGP42112A reduced the angiotensin II (Ang II)-mediated cell survival in both ovarian cancer cells and HUVEC. Combined treatment with losartan and CGP42112A synergistically decreased cell survival. As a downstream pathway, phosphorylation of phospholipase C β3 (PLC β3) and expression of vascular endothelial growth factor (VEGF) decreased synergistically in combined treatment.
  
  
  CONCLUSIONS
  The results suggest that dual regulation of AGTR1 and AGTR2 may be a novel therapeutic strategy for epithelial ovarian carcinoma through inhibition of cancer cell survival as well as anti-angiogenesis.
  
  
  CONCLUSIONS
  This study investigated the expressions of AGTR1 and AGTR2 in epithelial ovarian carcinoma and the therapeutic potential of AGTR modulation with specific antagonist and/or agonist in epithelial ovarian cancer cells. Treatment of AGTR1 antagonist, losartan and/or AGTR2 agonist, CGP42112A synergistically mediated anti-cancer effects including the decrease of cell survival and down-regulation of VEGF.
authors.affiliation: Department of Obstetrics and Gynecology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
authors.forename: Young-Ae
authors.initials: YA
authors.lastname: Park
authors.affiliation: Department of Obstetrics and Gynecology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
authors.forename: Chel Hun
authors.initials: CH
authors.lastname: Choi
authors.affiliation: Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
authors.forename: In-Gu
authors.initials: IG
authors.lastname: Do
authors.affiliation: Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
authors.forename: Sang Yong
authors.initials: SY
authors.lastname: Song
authors.affiliation: Department of Obstetrics and Gynecology, Korea University Guro Hospital, Korea University College of Medicine, Seoul, Republic of Korea.
authors.forename: Jae Kwan
authors.initials: JK
authors.lastname: Lee
authors.affiliation: Department of Obstetrics and Gynecology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
authors.forename: Young Jae
authors.initials: YJ
authors.lastname: Cho
authors.affiliation: Department of Obstetrics and Gynecology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
authors.forename: Jung-Joo
authors.initials: JJ
authors.lastname: Choi
authors.affiliation: Department of Obstetrics and Gynecology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
authors.forename: Hye Kyung
authors.initials: HK
authors.lastname: Jeon
authors.affiliation: Department of Obstetrics and Gynecology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
authors.forename: Ji Yoon
authors.initials: JY
authors.lastname: Ryu
authors.affiliation: Department of Obstetrics and Gynecology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
authors.forename: Yoo-Young
authors.initials: YY
authors.lastname: Lee
authors.affiliation: Department of Obstetrics and Gynecology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
authors.forename: Tae-Joong
authors.initials: TJ
authors.lastname: Kim
authors.affiliation: Department of Obstetrics and Gynecology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
authors.forename: Duk-Soo
authors.initials: DS
authors.lastname: Bae
authors.affiliation: Department of Obstetrics and Gynecology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea. Electronic address: garden.lee7@gmail.com.
authors.forename: Jeong-Won
authors.initials: JW
authors.lastname: Lee
authors.affiliation: Department of Obstetrics and Gynecology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea. Electronic address: huna0@naver.com.
authors.forename: Byoung-Gie
authors.initials: BG
authors.lastname: Kim
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000627:therapeutic use*; D000077216:Carcinoma, Ovarian Epithelial; D002478:Cells, Cultured; D018450:Disease Progression; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D019808:Losartan / Q000627:therapeutic use*; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D009375:Neoplasms, Glandular and Epithelial / Q000188:drug therapy*; D009842:Oligopeptides / Q000627:therapeutic use*; D010051:Ovarian Neoplasms / Q000188:drug therapy*; D044140:Receptor, Angiotensin, Type 1 / Q000096:biosynthesis*; D044139:Receptor, Angiotensin, Type 2 / Q000819:agonists* / Q000096:biosynthesis*
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D009842:Oligopeptides; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; C060894:CGP 42112A; D019808:Losartan
keywords: AGTR1; AGTR2; CGP42112A; Losartan; Ovarian carcinoma