Department of Obstetrics and Gynecology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
Gynecol Oncol. 2014 Oct;135(1):108-17. doi: 10.1016/j.ygyno.2014.06.031. Epub 2014 Jul 9.
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.
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).
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.
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.
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.
肾素-血管紧张素系统（RAS）影响心血管稳态，血管紧张素 II 型 1 型受体（AGTR1）是 RAS 的主要效应器，而 AGTR2 拮抗 AGTR1。越来越多的证据支持 RAS 在几种癌症类型的肿瘤发生的旁分泌调节中的作用。尽管用 AGTR1 拮抗剂（氯沙坦）或 AGTR2 激动剂（CGP42112A）治疗可抑制几种癌细胞的肿瘤进展，但尚未报道其联合治疗。
在本研究中，我们估计了上皮性卵巢癌细胞和组织中 AGTR1 和 AGTR2 的表达。然后，我们评估了联合使用氯沙坦和/或 CGP42112A 治疗卵巢癌细胞和人脐静脉内皮细胞（HUVEC）的抗癌效果。
AGTR1 蛋白在 86%的卵巢癌组织中被检测到，而免疫组织化学未检测到 AGTR2。癌症基因组图谱（TCGA）数据集获得的 AGTR1 mRNA 表达表明，AGTR1 过表达与预后不良相关。用氯沙坦或 CGP42112A 处理均可减少血管紧张素 II（Ang II）介导的卵巢癌细胞和 HUVEC 的细胞存活。氯沙坦和 CGP42112A 联合治疗协同降低细胞存活率。作为下游途径，磷酸化磷脂酶 Cβ3（PLCβ3）和血管内皮生长因子（VEGF）的表达协同降低。
结果表明，通过抑制癌细胞存活和抗血管生成，双重调节 AGTR1 和 AGTR2 可能成为上皮性卵巢癌的一种新的治疗策略。
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