Sphingosine-1-phosphate receptor type 1 regulates glioma cell proliferation and correlates with patient survival

Sphingosine-1-phosphate (S1P) is a bioactive lipid that signals through a family of G protein-coupled receptors consisting of 5 members termed S1P1–5, and it regulates cellular proliferation, migration and survival. We investigated the expression and role of S1P receptors in glioma. Human glioma expressed S1P1, S1P2, S1P3, and S1P5 by quantitative real-time PCR analysis. Expression of the S1P1 was significantly lower in glioblastoma than in the normal brain (p < 0.01) and diffuse astrocytoma (p < 0.05). Immunoblotting showed that normal brain expressed more S1P1 protein than did glioblastoma. Immunohistochemistry showed that S1P1 was localized predominantly in the astrocytes in the normal brain, but no staining was observed in glioblastoma. Downregulation of S1P1 expression correlated with poor survival of patients with glioblastoma (p < 0.05). S1P1 small interfering RNA promoted cell proliferation in high-expressor glioma cell lines (T98G, G112). Cell proliferation was promoted by the pertussis toxin, which deactivates Gi/o type of G proteins; the S1P1 is exclusively coupled to these proteins. Forced expression of the S1P1 in low-expressor cell lines (U87, U251) resulted in decreased cell growth and led to suppressed tumor growth in transplanted gliomas in vivo. Furthermore, we found a significant association between the S1P1 expression and early growth response-1, a transcriptional factor that exhibits tumor suppression in glioblastoma cells (p < 0.05). These data indicate that the downregulation of S1P1 expression enhances the malignancy of glioblastoma by increasing cell proliferation and correlates with the shorter survival of patients with glioblastoma.