Sphingosine-1-Phosphate as a Regulator of Hypoxia-Induced Factor-1α in Thyroid Follicular Carcinoma Cells

Sphingosine-1-phosphate (S1P) is a bioactive lipid, which regulates several cancer-related processes including migration and angiogenesis. We have previously shown S1P to induce migration of follicular ML-1 thyroid cancer cells. Hypoxia-induced factor-1 (HIF-1) is an oxygen-sensitive transcription factor, which adapts cells to hypoxic conditions through increased survival, motility and angiogenesis. Due to these properties and its increased expression in response to intratumoral hypoxia, HIF-1 is considered a significant regulator of tumor biology. We found S1P to increase expression of the regulatory HIF-1 alpha subunit in normoxic ML-1 cells. S1P also increased HIF-1 activity and expression of HIF-1 target genes. Importantly, inhibition or knockdown of HIF-1 alpha attenuated the S1P-induced migration of ML-1 cells. S1P-induced HIF-1 alpha expression was mediated by S1P receptor 3 (S1P(3)), G(i) proteins and their downstream effectors MEK, PI3K, mTOR and PKC beta I. Half-life measurements with cycloheximide indicated that S1P treatment stabilized the HIF-1 alpha protein. On the other hand, S1P activated translational regulators eIF-4E and p70S6K, which are known to control HIF-1 alpha synthesis. In conclusion, we have identified S1P as a non-hypoxic regulator of HIF-1 activity in thyroid cancer cells, studied the signaling involved in S1P-induced HIF-1 alpha expression and shown S1P-induced migration to be mediated by HIF-1.