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Sphingosine kinase 1 overexpression contributes to sunitinib resistance in clear cell renal cell carcinoma.

ABSTRACT: Sphingosine kinase 1 (SphK1) is the major source of the bioactive lipid and GPCR agonist sphingosine 1-phosphate (S1P). Although alterations in SphK1 expression and activity have been detected in various human malignancies, its potential molecular mechanisms in the development and sunitinib resistance of clear cell renal cell carcinoma (ccRCC) remain obscure. In this study, we aim to evaluate the clinical significance of SphK1 and to explore the therapeutic implications of combination approach for ccRCC patients. We identify upregulation of SphK1 significantly associated with poor prognosis of large cohort of ccRCC patients, which contributing to cell proliferation, colony formation, migration and survival. Suppression of SphK1 activity either by shRNA or pharmacologic inhibitior FTY720 suppresses cell growth in vitro and in vivo. A comprehensive phosphoprotein antibody array reveals that SphK1 overexpression promoted RCC progression by regulating the Akt/mTOR pathway. Moreover, FTY720 administration enhanced tumor growth inhibition effect of sunitinib treatment on RCC cells in vitro and in vivo. Our results unraveled that increased SphK1 kinase activation defines an important mechanism for sunitinib resistance, therefore contributes to tumour development and represents therapeutic targets for ccRCC.

SUBMITTER: Xu Y

PROVIDER: S-EPMC6279321 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Sphingosine kinase 1 overexpression contributes to sunitinib resistance in clear cell renal cell carcinoma.

Xu Yunze Y Dong Baijun B Wang Jianfeng J Zhang Jin J Xue Wei W Huang Yiran Y

Oncoimmunology 20180925 12

Sphingosine kinase 1 (SphK1) is the major source of the bioactive lipid and GPCR agonist sphingosine 1-phosphate (S1P). Although alterations in SphK1 expression and activity have been detected in various human malignancies, its potential molecular mechanisms in the development and sunitinib resistance of clear cell renal cell carcinoma (ccRCC) remain obscure. In this study, we aim to evaluate the clinical significance of SphK1 and to explore the therapeutic implications of combination approach f ...[more]

PMID: 30524898

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Project description:BackgroundAntiangiogenic agents that specifically target vascular endothelial growth factor receptor (VEGFR), such as sunitinib, have been utilized as the standard therapy for metastatic clear cell renal cell carcinoma (ccRCC) patients. However, most patients eventually show no responses to the targeted drugs, and the mechanisms for the resistance remain unclear. This study is aimed to identify pivotal molecules and to uncover their potential functions involved in this adverse event in ccRCC treatment.MethodsTwo datasets, GSE64052 and GSE76068, were obtained from the Gene Expression Omnibus (GEO) database. The differentially expressed genes (DEGs) were identified using the limma package in R software. The gene set enrichment analysis (GSEA) was conducted using clusterProfiler package. A protein-protein interaction (PPI) network was built using the STRING database and Cytoscape software. Kaplan-Meier survival curves were plotted using R software. qRT-PCR and Western blotting were used to detect the MX2 and pathway expression in RCC cell lines. Sunitinib-resistant cell lines were constructed, and loss-of-function experiments were conducted by knocking down MX2. All statistical analyses were performed using R version 3.6.1 and SPSS 23.0.ResultsA total of 760 DEGs were derived from two datasets in GEO database, and five hub genes were identified, among which high-level MX2 exhibited a pronounced correlation with poor overall survival (OS) in sunitinib-resistant ccRCC patients. Clinical correlation analysis and Gene Set Variation Analysis (GSVA) on MX2 showed that the upregulation of MX2 was significantly related to the malignant phenotype of ccRCC, and it was involved in several pathways and biological processes associated with anticancer drug resistance. qRT-PCR and Western blotting revealed that MX2 was distinctly upregulated in sunitinib-resistant RCC cell lines. Colony formation assay and Cell Counting Kit-8 (CCK8) assay showed that MX2 strongly promoted resistant capability to sunitinib of ccRCC cells.ConclusionMX2 is a potent indicator for sunitinib resistance and a therapeutic target in ccRCC patients.

Dataset Information

Sphingosine kinase 1 overexpression contributes to sunitinib resistance in clear cell renal cell carcinoma.

Publications

Sphingosine kinase 1 overexpression contributes to sunitinib resistance in clear cell renal cell carcinoma.

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