School of Medicine, College of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan, R.O.C.
Department of Surgery, Sijhih Cathay General Hospital, New Taipei City, Taiwan, R.O.C.
Cancer Genomics Proteomics. 2021 May-Jun;18(3):207-220. doi: 10.21873/cgp.20253.
Metastatic renal cell carcinoma (RCC) often develops resistance to first-line targeted therapy such as sunitinib. G-Protein-coupled estrogen receptor 1 (GPER1) agonist G-1 was recently reported to regulate RCC physiology but the role of G-1 in RCC tumorigenesis and sunitinib resistance remains largely unknown.
Parental and sunitinib-resistant 786-O cells were treated with GPER1 agonist G-1, and quantitative phosphoproteomics was performed. Bioinformatic analyses and validations, including immunoblotting, cell migration, and cell cycle distribution, were performed.
G-1 repressed cell proliferation and migration in both parental and sunitinib-resistant 786-O cells. Phosphoproteomic signatures, including phosphoinositide 3-kinase and protein kinase B (PI3K-AKT) as well as other pathways, were up-regulated in sunitinib-resistant cells but application of G-1 reversed this effect. Among phosphoprotein candidates, activating transcription factor 2 (ATF2) Thr69/71 phosphorylation was antagonistically regulated by sunitinib resistance and G-1.
Our results open up the possibility for managing RCC and sunitinib resistance by GPER1 agonist G-1 and its regulated pathways.
转移性肾细胞癌（RCC）常对舒尼替尼等一线靶向治疗产生耐药。最近有报道称，G 蛋白偶联雌激素受体 1（GPER1）激动剂 G-1 可调节 RCC 生理学，但 G-1 在 RCC 发生和舒尼替尼耐药中的作用仍知之甚少。
用 GPER1 激动剂 G-1 处理亲本和舒尼替尼耐药的 786-O 细胞，并进行定量磷酸化蛋白质组学分析。进行了生物信息学分析和验证，包括免疫印迹、细胞迁移和细胞周期分布。
G-1 抑制了亲本和舒尼替尼耐药的 786-O 细胞的增殖和迁移。磷酸化蛋白质组学特征，包括磷酸肌醇 3-激酶和蛋白激酶 B（PI3K-AKT）以及其他途径，在舒尼替尼耐药细胞中上调，但 G-1 的应用逆转了这种效应。在磷酸化蛋白候选物中，激活转录因子 2（ATF2）Thr69/71 磷酸化被舒尼替尼耐药和 G-1 拮抗调节。
我们的结果为通过 GPER1 激动剂 G-1 及其调控途径来管理 RCC 和舒尼替尼耐药提供了可能性。
