Dual targeting of angiotensin receptors (AGTR1 and AGTR2) in epithelial ovarian carcinoma

Young Ae Park, Chel Hun Choi, In Gu Do, Sang Yong Song, Jae Kwan Lee, Young Jae Cho, Jung Joo Choi, Hye Kyung Jeon, Ji Yoon Ryu, Yoo Young Lee, Tae Joong Kim, Duk Soo Bae, Jeong Won Lee, Byoung Gie Kim

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

Objective. The renin- angiotensin system (RAS) influences cardiovascular homeostasis, and Angiotensin II type 1 receptor (AGTR1) is themain 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 proteinwas detected in 86% of ovarian cancer tissues,while AGTR2was 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.

Conclusion. 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. Translational relevance. 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.

Original languageEnglish
Pages (from-to)108-117
Number of pages10
JournalGynecologic Oncology
Volume135
Issue number1
DOIs
Publication statusPublished - 2014 Jan 1

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Angiotensin Receptors
Carcinoma
Losartan
Cell Survival
Renin-Angiotensin System
Neoplasms
Ovarian Neoplasms
Therapeutics
Human Umbilical Vein Endothelial Cells
Vascular Endothelial Growth Factor A
Angiotensin Type 1 Receptor
Atlases
Type C Phospholipases
Angiotensin II
Carcinogenesis
Homeostasis
Down-Regulation
Immunohistochemistry
Phosphorylation
CGP 42112A

Keywords

  • AGTR1
  • AGTR2
  • CGP42112A
  • Losartan
  • Ovarian carcinoma

ASJC Scopus subject areas

  • Oncology
  • Obstetrics and Gynaecology

Cite this

Dual targeting of angiotensin receptors (AGTR1 and AGTR2) in epithelial ovarian carcinoma. / Park, Young Ae; Choi, Chel Hun; Do, In Gu; Song, Sang Yong; Lee, Jae Kwan; Cho, Young Jae; Choi, Jung Joo; Jeon, Hye Kyung; Ryu, Ji Yoon; Lee, Yoo Young; Kim, Tae Joong; Bae, Duk Soo; Lee, Jeong Won; Kim, Byoung Gie.

In: Gynecologic Oncology, Vol. 135, No. 1, 01.01.2014, p. 108-117.

Research output: Contribution to journalArticle

Park, YA, Choi, CH, Do, IG, Song, SY, Lee, JK, Cho, YJ, Choi, JJ, Jeon, HK, Ryu, JY, Lee, YY, Kim, TJ, Bae, DS, Lee, JW & Kim, BG 2014, 'Dual targeting of angiotensin receptors (AGTR1 and AGTR2) in epithelial ovarian carcinoma', Gynecologic Oncology, vol. 135, no. 1, pp. 108-117. https://doi.org/10.1016/j.ygyno.2014.06.031
Park, Young Ae ; Choi, Chel Hun ; Do, In Gu ; Song, Sang Yong ; Lee, Jae Kwan ; Cho, Young Jae ; Choi, Jung Joo ; Jeon, Hye Kyung ; Ryu, Ji Yoon ; Lee, Yoo Young ; Kim, Tae Joong ; Bae, Duk Soo ; Lee, Jeong Won ; Kim, Byoung Gie. / Dual targeting of angiotensin receptors (AGTR1 and AGTR2) in epithelial ovarian carcinoma. In: Gynecologic Oncology. 2014 ; Vol. 135, No. 1. pp. 108-117.
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AU - Lee, Jae Kwan

AU - Cho, Young Jae

AU - Choi, Jung Joo

AU - Jeon, Hye Kyung

AU - Ryu, Ji Yoon

AU - Lee, Yoo Young

AU - Kim, Tae Joong

AU - Bae, Duk Soo

AU - Lee, Jeong Won

AU - Kim, Byoung Gie

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AB - Objective. The renin- angiotensin system (RAS) influences cardiovascular homeostasis, and Angiotensin II type 1 receptor (AGTR1) is themain 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 proteinwas detected in 86% of ovarian cancer tissues,while AGTR2was 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.Conclusion. 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. Translational relevance. 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.

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