G-Protein-coupled Estrogen Receptor 1 Agonist G-1 Perturbs Sunitinib Resistance-related Phosphoproteomic Signatures in Renal Cell Carcinoma

Overview

Journal Cancer Genomics Proteomics

Specialties Biochemistry
Genetics
Oncology

Date 2021 Apr 24

PMID 33893075

Citations 3

Authors

Shao-Kuan Chen

Yen-Chieh Wang

Tai-Yuan Lin

Hsin-Jou Wu

Chi-Jung Huang

Wei-Chi Ku

Affiliations

Soon will be listed here.

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.

Citing Articles

Knockdown of G Protein-coupled Estrogen Receptor 1 (GPER1) Enhances Tumor-supportive Properties in Cervical Carcinoma Cells.

Ruckriegl S, Loris J, Wert K, Bauerschmitz G, Gallwas J, Grundker C Cancer Genomics Proteomics. 2023; 20(3):281-297.

PMID: 37093686 PMC: 10148066. DOI: 10.21873/cgp.20381.

Advances in Renal Cell Carcinoma Drug Resistance Models.

Xiang Y, Zheng G, Zhong J, Sheng J, Qin H Front Oncol. 2022; 12:870396.

PMID: 35619895 PMC: 9128023. DOI: 10.3389/fonc.2022.870396.

Establishment of Sunitinib-Resistant Xenograft Model of Renal Cell Carcinoma and the Identification of Drug-Resistant Hub Genes and Pathways.

Xie Y, Shangguan W, Chen Z, Zheng Z, Chen Y, Zhong Q Drug Des Devel Ther. 2021; 15:5061-5074.

PMID: 34938069 PMC: 8687523. DOI: 10.2147/DDDT.S343718.

References

Krug K, Mertins P, Zhang B, Hornbeck P, Raju R, Ahmad R . A Curated Resource for Phosphosite-specific Signature Analysis. Mol Cell Proteomics. 2018; 18(3):576-593. PMC: 6398202. DOI: 10.1074/mcp.TIR118.000943. View

Deutsch E, Csordas A, Sun Z, Jarnuczak A, Perez-Riverol Y, Ternent T . The ProteomeXchange consortium in 2017: supporting the cultural change in proteomics public data deposition. Nucleic Acids Res. 2016; 45(D1):D1100-D1106. PMC: 5210636. DOI: 10.1093/nar/gkw936. View

Makhov P, Joshi S, Ghatalia P, Kutikov A, Uzzo R, Kolenko V . Resistance to Systemic Therapies in Clear Cell Renal Cell Carcinoma: Mechanisms and Management Strategies. Mol Cancer Ther. 2018; 17(7):1355-1364. PMC: 6034114. DOI: 10.1158/1535-7163.MCT-17-1299. View

Cox J, Mann M . MaxQuant enables high peptide identification rates, individualized p.p.b.-range mass accuracies and proteome-wide protein quantification. Nat Biotechnol. 2008; 26(12):1367-72. DOI: 10.1038/nbt.1511. View

Niks M, Otto M . Towards an optimized MTT assay. J Immunol Methods. 1990; 130(1):149-51. DOI: 10.1016/0022-1759(90)90309-j. View

Butz H, Ding Q, Nofech-Mozes R, Lichner Z, Ni H, Yousef G . Elucidating mechanisms of sunitinib resistance in renal cancer: an integrated pathological-molecular analysis. Oncotarget. 2018; 9(4):4661-4674. PMC: 5797004. DOI: 10.18632/oncotarget.23163. View

Lu L, Li Y, Wen H, Feng C . Overexpression of miR-15b Promotes Resistance to Sunitinib in Renal Cell Carcinoma. J Cancer. 2019; 10(15):3389-3396. PMC: 6603409. DOI: 10.7150/jca.31676. View

Giurgiu M, Reinhard J, Brauner B, Dunger-Kaltenbach I, Fobo G, Frishman G . CORUM: the comprehensive resource of mammalian protein complexes-2019. Nucleic Acids Res. 2018; 47(D1):D559-D563. PMC: 6323970. DOI: 10.1093/nar/gky973. View

Dimayacyac-Esleta B, Tsai C, Kitata R, Lin P, Choong W, Lin T . Rapid High-pH Reverse Phase StageTip for Sensitive Small-Scale Membrane Proteomic Profiling. Anal Chem. 2015; 87(24):12016-23. DOI: 10.1021/acs.analchem.5b03639. View

10.

Ito H, Ichiyanagi O, Naito S, Bilim V, Tomita Y, Kato T . GSK-3 directly regulates phospho-4EBP1 in renal cell carcinoma cell-line: an intrinsic subcellular mechanism for resistance to mTORC1 inhibition. BMC Cancer. 2016; 16:393. PMC: 4936323. DOI: 10.1186/s12885-016-2418-7. View

11.

Bindea G, Mlecnik B, Hackl H, Charoentong P, Tosolini M, Kirilovsky A . ClueGO: a Cytoscape plug-in to decipher functionally grouped gene ontology and pathway annotation networks. Bioinformatics. 2009; 25(8):1091-3. PMC: 2666812. DOI: 10.1093/bioinformatics/btp101. View

12.

Geiger T, Wisniewski J, Cox J, Zanivan S, Kruger M, Ishihama Y . Use of stable isotope labeling by amino acids in cell culture as a spike-in standard in quantitative proteomics. Nat Protoc. 2011; 6(2):147-57. DOI: 10.1038/nprot.2010.192. View

13.

Xia Y, Liu L, Xiong Y, Bai Q, Wang J, Xi W . Prognostic value of CC-chemokine receptor seven expression in patients with metastatic renal cell carcinoma treated with tyrosine kinase inhibitor. BMC Cancer. 2017; 17(1):70. PMC: 5259971. DOI: 10.1186/s12885-017-3065-3. View

14.

Huang D, Sherman B, Lempicki R . Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc. 2009; 4(1):44-57. DOI: 10.1038/nprot.2008.211. View

15.

Hew M, Zonneveld R, Kummerlin I, Opondo D, de la Rosette J, Laguna M . Age and gender related differences in renal cell carcinoma in a European cohort. J Urol. 2012; 188(1):33-8. DOI: 10.1016/j.juro.2012.02.2573. View

16.

Sakai I, Miyake H, Fujisawa M . Acquired resistance to sunitinib in human renal cell carcinoma cells is mediated by constitutive activation of signal transduction pathways associated with tumour cell proliferation. BJU Int. 2013; 112(2):E211-20. DOI: 10.1111/j.1464-410X.2012.11655.x. View

17.

Chan Q, Lam H, Ng C, Lee A, Chan E, Ng H . Activation of GPR30 inhibits the growth of prostate cancer cells through sustained activation of Erk1/2, c-jun/c-fos-dependent upregulation of p21, and induction of G(2) cell-cycle arrest. Cell Death Differ. 2010; 17(9):1511-23. PMC: 2897932. DOI: 10.1038/cdd.2010.20. View

18.

Smith L, Ralston-Hooper K, Ferguson P, Sabo-Attwood T . The G Protein-Coupled Estrogen Receptor Agonist G-1 Inhibits Nuclear Estrogen Receptor Activity and Stimulates Novel Phosphoproteomic Signatures. Toxicol Sci. 2016; 151(2):434-46. PMC: 4880142. DOI: 10.1093/toxsci/kfw057. View

19.

Marech I, Gadaleta C, Ranieri G . Possible prognostic and therapeutic significance of c-Kit expression, mast cell count and microvessel density in renal cell carcinoma. Int J Mol Sci. 2014; 15(7):13060-76. PMC: 4139891. DOI: 10.3390/ijms150713060. View

20.

Siegel R, Miller K, Jemal A . Cancer statistics, 2020. CA Cancer J Clin. 2020; 70(1):7-30. DOI: 10.3322/caac.21590. View