Sphingosine Kinase as an Oncogene: Autocrine Sphingosine 1-Phoshate Modulates ML-1 Thyroid Carcinoma Cell Migration by a Mechanism Dependent on Protein Kinase C-α and ERK1/2
Sphingosine Kinase as an Oncogene: Autocrine Sphingosine 1-Phoshate Modulates ML-1 Thyroid Carcinoma Cell Migration by a Mechanism Dependent on Protein Kinase C-α and ERK1/2
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DOI：
10.1210/en.2008-0625
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发表时间：
2009-05-01
期刊：
影响因子：
4.8
通讯作者：
Toernquist, K.
中科院分区：
文献类型：
--
作者：
Bergelin, N.;Blom, T.;Toernquist, K.
Sphingosine 1-phosphate （S1P）通过激活S1P(1)和S1P(3)受体、G(1)蛋白以及磷脂酰肌醇3-激酶- akt通路诱导人甲状腺滤泡癌细胞ML-1的迁移。由于鞘氨醇激酶异构体1 （SK）最近被认为是多种癌细胞系统中的致癌基因，我们研究了SK在ML-1细胞系的迁移、增殖和粘附中的功能。SK过表达ML-1的细胞显示S1P分泌增强，可通过抑制SK活性和多药耐药转运蛋白（atp结合盒转运蛋白）来减弱S1P分泌。此外，SK的过表达增强了血清诱导的ML-1细胞迁移，可通过阻断atp结合盒转运体和SK来减弱迁移，这表明迁移是通过分泌S1P的自分泌信号介导的。用小干扰RNA （siRNA）和小分子抑制剂抑制蛋白激酶C α可减弱SK过表达细胞的迁移。此外，与表达显性阴性SK的细胞相比，SK过表达的细胞表现出粘附受损、细胞生长缓慢和ERK1/2磷酸化上调。综上所述，我们提供的证据表明，SK通过自分泌机制增强了ML-1细胞的迁移，而SK诱发的迁移依赖于蛋白激酶C α、ERK1/2和SK。（内分泌学150:2055-2063,2009）
Sphingosine 1-phosphate (S1P) induces migration of the human thyroid follicular carcinoma cell line ML-1 by activation of S1P(1) and S1P(3) receptors, G(1) proteins, and the phosphatidylinositol 3-kinase-Akt pathway. Because sphingosine kinase isoform 1 (SK) recently has been implicated as an oncogene in various cancer cell systems, we investigated the functions of SK in the migration, proliferation and adhesion of the ML-1 cell line. SK overexpressing ML-1 cells show an enhanced secretion of S1P, which can be attenuated, by inhibiting SK activity and a multidrug-resistant transport protein (ATP-binding cassette transporter). Furthermore, overexpression of SK enhances serum-induced migration of ML-1 cells, which can be attenuated by blocking ATP-binding cassette transporter and SK, suggesting that the migration is mediated by autocrine signaling through secretion of S1P. Inhibition of protein kinase C alpha, with both small interfering RNA (siRNA) and small molecular inhibitors attenuates migration in SK overexpressing cells. In addition, SK-overexpressing cells show an impaired adhesion, slower cell growth, and an up-regulation of ERK1/2 phosphorylation, as compared with cells expressing a dominant-negative SK. Taken together, we present evidence suggesting that SK enhances migration of ML-1 cells by an autocrine mechanism and that the S1P-evoked migration is dependent on protein kinase C alpha, ERK1/2, and SK. (Endocrinology 150: 2055-2063, 2009)