Sphingosine kinase 1 overexpression contributes to sunitinib resistance in clear cell renal cell carcinoma
Sphingosine kinase 1 overexpression contributes to sunitinib resistance in clear cell renal cell carcinoma
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DOI：
10.1080/2162402x.2018.1502130
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发表时间：
2018-12-02
期刊：
影响因子：
7.2
通讯作者：
Huang, Yiran
中科院分区：
文献类型：
--
作者：
Xu, Yunze;Dong, Baijun;Huang, Yiran
鞘氨醇激酶1（SphK 1）是生物活性脂质和GPCR激动剂鞘氨醇1-磷酸（S1 P）的主要来源。虽然SphK 1表达和活性的改变已在各种人类恶性肿瘤中检测到，但其在透明细胞肾细胞癌（ccRCC）发展和舒尼替尼耐药中的潜在分子机制仍不清楚。在这项研究中，我们的目的是评估SphK 1的临床意义，并探讨联合方法对ccRCC患者的治疗意义。我们确定SphK 1的上调与大队列ccRCC患者的不良预后显著相关，其有助于细胞增殖、集落形成、迁移和存活。通过shRNA或药物抑制剂FTY 720抑制SphK 1活性在体外和体内抑制细胞生长。一个全面的磷蛋白抗体阵列显示SphK 1过表达通过调节Akt/mTOR通路促进RCC进展。此外，FTY 720给药增强了舒尼替尼治疗对RCC细胞的体外和体内肿瘤生长抑制作用。我们的研究结果揭示了SphK 1激酶激活的增加定义了舒尼替尼耐药的重要机制，因此有助于肿瘤的发展，并代表了ccRCC的治疗靶点。
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.