Abstract
In anaplastic thyroid cancer C643 cells, sphingosine 1-phosphate (S1P) attenuates migration by activating the S1P2 receptor and the Rho-ROCK pathway. In the present study, we show that stimulating C643 cells with S1P decreases the expression, secretion and activity of matrix metalloproteinase-2 (MMP2), and to a lesser extent MMP9. Using receptor-specific antagonists, and S1P2 siRNA, we showed that the inhibition of expression of MMP2 is mediated through S1P2. Furthermore, S1P inhibited calpain activity, and inhibiting calpain pharmacologically, inhibited the effect of S1P on MMP2 expression and activity, and on MMP9 activity. S1P treatment increased Rho activity, and by incubating cells with the Rho inhibitor C3 transferase or the ROCK inhibitor Y27632, the S1P-induced inhibition of invasion and MMP2 expression and activity was abolished. We conclude that S1P attenuates the invasion of C643 cells by activating S1P2 and the Rho-ROCK pathway, by decreasing calpain activity, and by decreasing the expression, secretion and activity of MMP2 and, to a lesser extent, MMP9. Our results thus unveil a novel function for the S1P2 receptor in attenuating thyroid cancer cell invasion.
Highlights
Sphingosine 1-phosphate (S1P), a bioactive lipid, is a regulator of many cellular processes, including cancer cell invasion and migration [1]
We show that sphingosine 1-phosphate (S1P) potently attenuates the expression, secretion and activity of matrix metalloproteinase-2 (MMP2), and to a lesser degree, the secretion and activity of MMP9
This is a novel mechanism by which the anti-migratory receptor S1P2 can convey its effects on cells, and is, in part, a mechanism mediating the inhibitory effect of S1P2 on invasion
Summary
Sphingosine 1-phosphate (S1P), a bioactive lipid, is a regulator of many cellular processes, including cancer cell invasion and migration [1]. In many cancer cells, including follicular thyroid cancer ML-1 cells, S1P promotes migration and invasion by activating S1P1,3 and downstream PI3K-Akt and Rac signaling pathways [3,4,5,6,7,8]. S1P inhibits migration and invasion by activating S1P receptor 2 and the downstream Rho-ROCK signaling pathway and by inhibiting Rac activity in many cell types [9], including human anaplastic thyroid cancer C643 cells [10]. The small GTP-ase Rac promotes invasion [12] and has been shown to regulate S1P-evoked matrix metalloproteinase 2 and -9 (MMP2 and -9) secretion in cancer cells [13].
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