Targeting sphingosine kinase 2 by ABC294640 inhibits human skin squamous cell carcinoma cell growth.

The activity of ABC294640, a small-molecular sphingosine kinase 2 (SphK2) inhibitor, in human skin squamous cell carcinoma (SCC) cells was tested in this study. SphK2 mRNA and protein are expressed in established (A431 cheilocarcinoma cell line) and primary human skin SCC cells. ABC294640 dose-dependently inhibited survival, cell cycle progression and proliferation of skin SCC cells. Furthermore, ABC294640 induced caspase-3/-9 and apoptosis activation in skin SCC cells. The SphK2 inhibitor was however non-cytotoxic to SphK2-null skin melanocytes, keratinocytes and fibroblasts. ABC294640 induced ceramide accumulation, sphingosine-1-phosphate (S1P) reduction, Akt-S6K1 inhibition and JNK activation in skin SCC cells. Conversely, its cytotoxicity against SCC cells was largely attenuated by co-treatment of S1P, the Akt activator SC79, and the JNK inhibitor SP600125. In vivo, ABC294640 oral administration inhibited A431 xenograft tumor growth in nude mice. Akt-S6K1 inhibition and JNK activation were observed in ABC294640-treated tumors. Collectively, ABC294640 efficiently inhibits human skin SCC cell growth in vitro and in vivo.