The sphingosine kinase 2 inhibitor ABC294640 reduces the growth of prostate cancer cells and results in accumulation of dihydroceramides in vitro and in vivo

Abstract

Despite recent advances in the development of novel therapies against castration-resistant prostate cancer, the advanced form of the disease remains a major treatment challenge. Aberrant sphingolipid signaling through sphingosine kinases and their product, sphingosine-1-phosphate, can promote proliferation, drug resistance, angiogenesis, and inflammation. The sphingosine kinase 2 inhibitor ABC294640 is undergoing clinical testing in cancer patients, and in this study we investigated the effects this firstin-class inhibitor in castration-resistant prostate cancer. In vitro, ABC294640 decreased prostate cancer cell viability as well as the expression of c-Myc and the androgen receptor, while lysosomal acidification increased. ABC294640 also induced a greater than 3- fold increase in dihydroceramides that inversely correlated with inhibition of dihydroceramide desaturase (DEGS) activity. Expression of sphingosine kinase 2 was dispensable for the ABC294640-mediated increase in dihydroceramides. In vivo, ABC294640 diminished the growth rate of TRAMP-C2 xenografts in syngeneic hosts and elevated dihydroceramides within tumors as visualized by MALDI imaging mass spectroscopy. The plasma of ABC294640-treated mice contained significantly higher levels of C16- and C24:1-ceramides (but not dihydro-C16-ceramide) compared with vehicle-treated mice. In summary, our results suggest that ABC294640 may reduce the proliferative capacity of castration-resistant prostate cancer cells through inhibition of both sphingosine kinase 2 and dihydroceramide desaturase, thereby providing a foundation for future exploration of this small-molecule inhibitor for the treatment of advanced disease.