Sphingosine kinases are involved in the regulation of all-trans retinoic acid sensitivity of K562 chronic myeloid leukemia cells

The efficacy of all-trans retinoic acid (ATRA) for the treatment of chronic myeloid leukemia (CML) has been reported to be limited both as single-drug treatment or in combination with other drugs. Our previous study demonstrated that sphingosine 1-phosphate attenuated the effects of ATRA on human colon cancer cells by blocking the expression of retinoic acid receptor beta. The aim of the present study was to investigate whether the ATRA-dependent proliferation inhibition of K562 cells was regulated by sphingosine kinases (SphKs). The results of cell proliferation assay and reverse transcription-PCR demonstrated that ATRA may exert synergistic effects with the SphK1 inhibitor SKI 5C or the pan-SphK inhibitor SKI II to inhibit the proliferation of K562 cells and upregulate the expression levels of the ATRA-inducible enzyme cytochrome P450 26A1 (CYP26A1). Knocking down the expression of SphK1 or SphK2 in K562 cells by small interfering RNA enhanced the inhibitory effects of ATRA and induced the expression of CYP26A1. Crude asterosaponins, which abrogated the expression of SphK2, also enhanced the effects of ATRA on K562 cells. In conclusion, the results of the present study demonstrated that SphKs may be involved in the regulation of the sensitivity of CML cells to ATRA.