Dataset Information

Quantitative phosphoproteomics of chronic sunitinib treated renal cell carcinoma 786-O cells with GPR30 agonist G-1

ABSTRACT: In this project, we generated chronic sunitinib-treated 786-O cell, a renal cell carcinoma cell line. In order to investigate the possible effect of GPR30 agonist, G-1, on the growth-inhibtion related signaling pathways, we treated either parental both parental and chronic sunitinib-treated 786-O cells were treated either by vehicle-only (i.e. 0.1% DMSO) or 2 μM G-1 for 48 h. Therefore, there were three groups for comparison, including G-1 treatment (G-1 vs. parental), chronic sunitinib-treatment (SunR vs. parental), and G-1 treatment in SunR cells (SunR&G-1 vs. parental).

INSTRUMENT(S): LTQ Orbitrap XL

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Epithelial Cell, Cell Culture

DISEASE(S): Renal Cell Carcinoma

SUBMITTER: Wei-Chi Ku

LAB HEAD: Wei-Chi Ku

PROVIDER: PXD021254 | Pride | 2021-04-28

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	160831-786ODMSO7860-RDMSO-03-GA1-1.raw	Raw
	160831-786ODMSO7860-RDMSO-04-GA1-2.raw	Raw
	160831-786ODMSO7860-RDMSO-05-GA2-1.raw	Raw
	160831-786ODMSO7860-RDMSO-06-GA2-2.raw	Raw
	160831-786ODMSO7860-RDMSO-07-GA3-1.raw	Raw

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Publications

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

Chen Shao-Kuan SK Wang Yen-Chieh YC Lin Tai-Yuan TY Wu Hsin-Jou HJ Huang Chi-Jung CJ Ku Wei-Chi WC

Cancer genomics & proteomics 20210501 3

<h4>Background</h4>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.<h4>Materials and methods</h4>Parental and sunitinib-resistant 786-O cells were treated with GPER1 agonist G-1, and quantitative phosphoproteomics was performed. Bioinfor ...[more]

PMID: 33893075

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Project description:Transcriptome analysis was used to identify gene expression changes during development of sunitinib resistance in a renal cell carcinoma patient-derived xenograft (PDX) model. During the response phase, tumors exhibited a 91% reduction in volume, characterized by induction of TNFRSF1A, TNFAIP3, NFKB2, CCL2, CCL20, BIRC3, and MOAP1. Ingenuity Pathway Analysis indicated decreased expression of cell survival genes during tumor response to sunitinib. In this model, after 4 weeks of treatment, tumors developed resistance despite continued administration of the tyrosine kinase inhibitor (TKI) sunitinib (40 mg/kg/d p.o.). Resistance was associated with increased expression of VEGFA, EPO, IL-8, ANGPT2, TNFRSF12, MAPK3/7, MAPKBP1, and increased cell survival genes, suggesting activation of angiogenesis and MAPK/ERK pathways. Tumor lysate mRNA evaluated for murine gene expression to examine the contribution of host effects, indicated that tumor response was associated with downregulation of immune cell trafficking, cellular movement, and inflammatory response genes. During tumor escape, genes associated with cellular movement, inflammatory response, and immune cell trafficking were strongly induced, along with intratumoral accumulation of myeloid derived suppressor cells (MDSC), indicating a role for host factors during emergence of sunitinib resistance. The same PDX model was used to assess anti-tumor efficacy of sunitinib combined with MEK inhibitor (MEKi) PD-0325901 (4 mg/kg/d p.o.) using different schedules. The most effective treatment regimen was either continuous treatment with both drugs or switching from sunitinib to PD-0325901 monotherapy at d30, which reduced tumor volume by 78.6% (p=0.0241) and 88.5% (p=0.0068), respectively. The combination of MEKi with TKI (sunitinib, axitinib, or pazopanib) suppressed levels of phospho-MEK1/2 and phospho-ERK1/2, and decreased intratumoral MDSC. Thus, continuous treatment with sunitinib alone did not maintain tumor response, and addition of a MEKi abrogated resistance leading to prolonged survival. Study was comprised of three experimental groups (pre-treatment, response, escape). All tumors came from the same PDX model. There were four biological replicates in each group. Four mice were used, with each of the 3 groups per mouse. There were no control or reference samples.