Kalhori Veronica, Magnusson Melissa, Asghar Muhammad Yasir, Pulli Ilari, Törnquist Kid
Department of BiosciencesÅbo Akademi University, Turku, Finland The Minerva Foundation Institute for Medical ResearchBiomedicum Helsinki, Helsinki, Finland.
Department of BiosciencesÅbo Akademi University, Turku, Finland.
Endocr Relat Cancer. 2016 May;23(5):457-68. doi: 10.1530/ERC-16-0050. Epub 2016 Mar 2.
The bioactive lipid sphingosine-1-phosphate (S1P) is a potent inducer of ML-1 thyroid cancer cell migration and invasion. It evokes migration and invasion by activating S1P receptor 1 and 3 (S1P1,3) and downstream signaling intermediates as well as through cross-communication with vascular endothelial growth factor receptor 2 (VEGFR2). However, very little is known about the role of S1P receptors in thyroid cancer. Furthermore, the currently used treatments for thyroid cancer have proven to be rather unsuccessful. Thus, due to the insufficiency of the available treatments for thyroid cancer, novel and targeted therapies are needed. The S1P receptor functional antagonist FTY720, an immunosuppressive drug currently used for treatment of multiple sclerosis, has shown promising effects as an inhibitor of cancer cell proliferation and invasion. In this study, we investigated the effect of FTY720 on invasion and proliferation of several thyroid cancer cell lines. We present evidence that FTY720 attenuated basal as well as S1P-evoked invasion of these cell lines. Furthermore, FTY720 potently downregulated S1P1, protein kinase Cα(PKCα), PKCβI, and VEGFR2. It also attenuated S1P-evoked phosphorylation of ERK1/2. Our results also showed that FTY720 attenuated S1P-induced MMP2 intracellular expression, S1P-induced secretion of MMP2 and MMP9, and decreased basal MMP2 and MMP9 activity. Moreover, in FTY720-treated cells, proliferation was attenuated, p21 and p27 were upregulated, and the cells were arrested in the G1 phase of the cell cycle. FTY720 attenuated cancer cell proliferation in the chick embryo chorioallantoic membrane assay. Thus, we suggest that FTY720 could be beneficial in the treatment of thyroid cancer.
生物活性脂质鞘氨醇-1-磷酸（S1P）是ML-1甲状腺癌细胞迁移和侵袭的有效诱导剂。它通过激活S1P受体1和3（S1P1,3）及下游信号中间体，以及通过与血管内皮生长因子受体2（VEGFR2）的交叉通讯来引发迁移和侵袭。然而，关于S1P受体在甲状腺癌中的作用知之甚少。此外，目前用于治疗甲状腺癌的方法已被证明相当不成功。因此，由于现有甲状腺癌治疗方法的不足，需要新的靶向治疗方法。S1P受体功能拮抗剂FTY720是一种目前用于治疗多发性硬化症的免疫抑制药物，已显示出作为癌细胞增殖和侵袭抑制剂的有前景的效果。在本研究中，我们研究了FTY720对几种甲状腺癌细胞系侵袭和增殖的影响。我们提供的证据表明，FTY720减弱了这些细胞系的基础侵袭以及S1P引发的侵袭。此外，FTY720强烈下调S1P1、蛋白激酶Cα（PKCα）、PKCβI和VEGFR2。它还减弱了S1P引发的ERK1/2磷酸化。我们的结果还表明，FTY720减弱了S1P诱导的MMP2细胞内表达、S1P诱导的MMP2和MMP9分泌，并降低了基础MMP2和MMP9活性。此外，在经FTY720处理的细胞中，增殖减弱，p21和p27上调，细胞停滞在细胞周期的G1期。FTY720在鸡胚绒毛尿囊膜试验中减弱了癌细胞增殖。因此，我们认为FTY720可能对甲状腺癌治疗有益。
