FTY720 (Fingolimod) attenuates basal and sphingosine-1-phosphate-evoked thyroid cancer cell invasion

Abstract

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 (S1P 1,3 ) 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 S1P 1 , protein kinase C α (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.

Comparison of Polydopamine-Coated Mesoporous Silica Nanorods and Spheres for the Delivery of Hydrophilic and Hydrophobic Anticancer Drugs

“…FTY720 is a prodrug, hence after administration it is converted to its active form, and acts as a functional antagonist in lymphocytes and downregulates the gene expression [23,24]. The in vitro investigation of FTY720 to inhibit the migration and attenuate the proliferation of follicular thyroid cancer ML-1 cells proved to be successful in studies by Kalhori et al [26], and met our goals as an efficient drug model on ML-1 cells.…”

“…Cytotoxicity of FTY720-loaded particles was determined by crystal violet assay in ML-1 cells, as they are thyroid carcinoma cells and have shown sensitivity towards FTY720 [26]. ML-1 cells were treated with empty and FTY720-loaded S-MSN@PDA and R-MSN@PDA and corresponding concentrations of free FTY720 (5, 8, and, 10 µM).…”

Sphingosine kinase 1 overexpression induces MFN2 fragmentation and alters mitochondrial matrix Ca2+ handling in HeLa cells

“…Corning Transwell membrane inserts were employed to study cell migration according to a protocol modified from [72]. Briefly, 75,000 cells were collected in serum-free medium and allowed to migrate through uncoated Transwell membrane inserts for 12 h. Fetal bovine serum (FBS) was utilized as a chemoattractant.…”

“…Briefly, 75,000 cells were collected in serum-free medium and allowed to migrate through uncoated Transwell membrane inserts for 12 h. Fetal bovine serum (FBS) was utilized as a chemoattractant. Then, the membranes were processed as described in [72] and the migrated cells were manually counted. The normalized cell counts were statistically analysed.…”

The avian chorioallantoic membrane as an alternative tool to study medullary thyroid cancer

“…Wide ranges of tumours, including thyroid cancers, have been studied using CAM (8, 9, 10, 11, 12). Yalcin et al .…”