Shao-Kuan Chen1,2, Yen-Chieh Wang1,3, Tai-Yuan Lin1, Hsin-Jou Wu1, Chi-Jung Huang4,5, Wei-Chi Ku6. 1. School of Medicine, College of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan, R.O.C. 2. Department of Surgery, Sijhih Cathay General Hospital, New Taipei City, Taiwan, R.O.C. 3. Division of Urology, Cathay General Hospital, Taipei City, Taiwan, R.O.C. 4. Department of Medical Research, Cathay General Hospital, Taipei City, Taiwan, R.O.C. 5. Department of Biochemistry, National Defense Medical Center, Taipei City, Taiwan, R.O.C. 6. School of Medicine, College of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan, R.O.C.; 089052@mail.fju.edu.tw.
Abstract
BACKGROUND: 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. MATERIALS AND METHODS: 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. RESULTS: 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. CONCLUSION: Our results open up the possibility for managing RCC and sunitinib resistance by GPER1 agonist G-1 and its regulated pathways. Copyright
BACKGROUND: 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. MATERIALS AND METHODS: 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. RESULTS: 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. CONCLUSION: Our results open up the possibility for managing RCC and sunitinib resistance by GPER1 agonist G-1 and its regulated pathways. Copyright
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