Synergistic effects of sphingosine kinase 1 inhibitors and anti-neoplastic agents on melanoma cell apoptosis

Sphingosine kinase 1 (SPHK1), a key enzyme in sphingosine 1-phosphate (S1P) synthesis, regulates various aspects of cell behavior, including cell survival and proliferation. DNA damaging anti-neoplastic agents have been shown to induce p53, ceramide, and apoptosis; however, the effects of anti-neoplastic agents on SPHK1 have not been fully assessed. Moreover, it is unknown what agents decrease the function of SPHK1 in melanoma cells. In this study, we investigated the effect of cisplatin, a DNA damaging agent, and its combined effect with FTY720, S1P receptor antagonist, or SK inhibitor (SKI) on the production and function of SPHK1 in cultured melanoma cells. Western blot analysis showed that cisplatin caused a reduction in SPHK1 at protein level. This down-regulation was post-transcriptional, because the mRNA level of SPHK1 by real time PCR was not suppressed. As a result, apoptosis was accelerated, as indicated by caspase 3/7 fluorophotometry. Furthermore, the combination of FTY720 or SKI with cisplatin caused additional increase in apoptosis. A decrease in SPHK1 may be necessary in part for apoptosis in melanoma cells. These results demonstrate that the combination of anti-neoplastic agents and FTY720 or SKI shows a synergistic effectiveness on apoptosis in cultured melanoma cells. It is expected that the combination of FTY720 or SKI with anti-neoplastic agents can be one of the effective therapies to reduce the doses of anti-neoplastic agents and to decrease the side effects of anti-neoplastic agents in chemotherapy for malignant melanoma. JSID AbstractsJournal of Dermatological ScienceVol. 69Issue 2Preview Full-Text PDF