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

doi:10.1016/j.ygyno.2014.06.031

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 journal › Article › peer-review

29 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 language	English
Pages (from-to)	108-117
Number of pages	10
Journal	Gynecologic Oncology
Volume	135
Issue number	1
DOIs	https://doi.org/10.1016/j.ygyno.2014.06.031
Publication status	Published - 2014 Oct 1
Externally published	Yes

Bibliographical note

Funding Information:
This study was supported by a grant from the Korea Healthcare Technology R&D Project, Ministry for Health & Welfare Affairs, Republic of Korea ( A092255 ), by the National R&D Program for Cancer Control, Ministry for Health, Welfare and Family affairs, Republic of Korea ( 0920010 ) and by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Republic of Korea ( 2013R1A1A2013629 ).

Publisher Copyright:
© 2014 Elsevier Inc.

Keywords

AGTR1
AGTR2
CGP42112A
Losartan
Ovarian carcinoma

ASJC Scopus subject areas

Oncology
Obstetrics and Gynaecology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.ygyno.2014.06.031

Cite this

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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 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.",

keywords = "AGTR1, AGTR2, CGP42112A, Losartan, Ovarian carcinoma",

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

note = "Funding Information: This study was supported by a grant from the Korea Healthcare Technology R&D Project, Ministry for Health & Welfare Affairs, Republic of Korea ( A092255 ), by the National R&D Program for Cancer Control, Ministry for Health, Welfare and Family affairs, Republic of Korea ( 0920010 ) and by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Republic of Korea ( 2013R1A1A2013629 ). Publisher Copyright: {\textcopyright} 2014 Elsevier Inc.",

year = "2014",

month = oct,

day = "1",

doi = "10.1016/j.ygyno.2014.06.031",

language = "English",

volume = "135",

pages = "108--117",

journal = "Gynecologic Oncology",

issn = "0090-8258",

publisher = "Academic Press Inc.",

number = "1",

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TY - JOUR

T1 - Dual targeting of angiotensin receptors (AGTR1 and AGTR2) in epithelial ovarian carcinoma

AU - Park, Young Ae

AU - Choi, Chel Hun

AU - Do, In Gu

AU - Song, Sang Yong

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

N1 - Funding Information: This study was supported by a grant from the Korea Healthcare Technology R&D Project, Ministry for Health & Welfare Affairs, Republic of Korea ( A092255 ), by the National R&D Program for Cancer Control, Ministry for Health, Welfare and Family affairs, Republic of Korea ( 0920010 ) and by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Republic of Korea ( 2013R1A1A2013629 ). Publisher Copyright: © 2014 Elsevier Inc.

PY - 2014/10/1

Y1 - 2014/10/1

N2 - 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.

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.

KW - AGTR1

KW - AGTR2

KW - CGP42112A

KW - Losartan

KW - Ovarian carcinoma

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SN - 0090-8258

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

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

UN SDGs

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