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G-Protein-coupled Estrogen Receptor 1 Agonist G-1 Perturbs Sunitinib Resistance-related Phosphoproteomic Signatures
Shao-Kuan Chen1,2, Yen-Chieh Wang1,3, Tai-Yuan Lin1
1School of Medicine, College of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan, R.O.C.
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.
Insights
G-1, a G-Protein-coupled estrogen receptor 1 (GPER1) agonist, effectively reduced renal cell carcinoma (RCC) proliferation and migration. G-1 also reversed sunitinib resistance by modulating key signaling pathways, offering a potential therapeutic strategy.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Metastatic renal cell carcinoma (RCC) frequently develops resistance to targeted therapies like sunitinib.
- The role of G-Protein-coupled estrogen receptor 1 (GPER1) agonist G-1 in RCC tumorigenesis and sunitinib resistance is largely unexplored.
Purpose of the Study:
- To investigate the effect of GPER1 agonist G-1 on renal cell carcinoma (RCC) cells, particularly in the context of sunitinib resistance.
- To elucidate the molecular mechanisms underlying G-1's action in sunitinib-resistant RCC.
Main Methods:
- Quantitative phosphoproteomics was employed on parental and sunitinib-resistant 786-O RCC cells treated with G-1.
- Bioinformatic analyses, immunoblotting, cell migration assays, and cell cycle distribution analyses were performed for validation.
Main Results:
- G-1 inhibited cell proliferation and migration in both parental and sunitinib-resistant 786-O cells.
- G-1 reversed the upregulation of phosphoinositide 3-kinase and protein kinase B (PI3K-AKT) pathway signatures observed in sunitinib-resistant cells.
- Activating transcription factor 2 (ATF2) phosphorylation at Thr69/71 was found to be antagonistically regulated by sunitinib resistance and G-1 treatment.
Conclusions:
- GPER1 agonist G-1 demonstrates potential as a therapeutic agent for managing RCC.
- G-1 may offer a novel strategy to overcome sunitinib resistance in RCC by targeting specific signaling pathways.
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