Evidence Suggests Sphingosine 1-Phosphate Might Be Actively Generated, Degraded, and Transported to Extracellular Spaces With Increased S1P2 and S1P3 Expression in Colon Cancer

In colon cancer tissues, mRNA expression of not only generating enzymes but also degrading enzymes, transporters, and receptors of sphingosine 1-phosphate (S1P), a prosurvival factor, was increased, with unexpectedly unaltered levels of S1P. Enhanced expression of S1P-degrading enzymes in colon cancer cell lines was associated with active proliferation, and reduced expression was associated with decreased proliferation. Active S1P metabolism and movement might play a role in colon cancer pathophysiology. Background: A pivotal role of sphingosine 1-phosphate (S1P) in cancer has been suggested based on the ceramide-S1P rheostat theory that the intracellular balance between prosurvival S1P and proapoptotic ceramide determines cell fate. Upregulation of S1P-generating sphingosine kinases (SKs) and downregulation of S1P-degrading S1P lyase (SPL) might increase intracellular S1P levels to exert a prosurvival effect in cancer in general, such as colon cancer. However, we recently observed a distinct S1P metabolism in hepatocellular carcinoma tissues that increased SPL mRNA levels with reduced S1P levels. Thus, we investigated S1P metabolism in colon cancer. Patients and Methods: We enrolled 26 consecutive colon cancer patients, who had undergone surgical treatment. Results: Not only SK, but also SPL, mRNA levels were increased in colon cancer tissues compared with the adjacent nontumorous tissues. Furthermore, the mRNA levels of another S1P degrading enzyme, S1P phosphatase 1, S1P transporters, spinster homolog 2, adenosine triphosphate-binding cassette subfamily C member 1, and S1P receptors, S1P(2) and S1P(3) were also increased, but the S1P levels were not increased in the colon cancer tissues. The reduction of SPL expression by silencing led to reduced proliferation and invasion, and overexpression of SPL caused enhanced proliferation in colon cancer cell lines. Conclusion: In human colon cancer tissues, mRNA levels of S1P-generating and S1P-degrading enzymes, transporters from inside to outside the cells, and S1P receptors, S1P(2) and S1P(3) were elevated, suggesting active S1P metabolism and movement. This altered S1P metabolism might play a role in colon cancer pathophysiology.