Inhibition of ceramide kinase is effectively against cisplatin-resistant ovarian cancer cells by regulating ceramide and C1P levels.

OBJECTIVE: Chemoresistance in ovarian cancer results in treatment failure, yet underlying mechanisms that regulate chemoresistance remain largely unclear. There is emerging evidence relating ovarian cancer drug resistance with bioactive sphingolipids and regulation of sphingolipid metabolism. This work investigated the expression and function of ceramide kinase (CerK), a lipid kinase that regulate central bioactive sphingolipids, in ovarian cancer, as well as the therapeutic potential of targeting CERK.

DESIGN: The level of ceramide, C1P and Cerk in ovarian cancer and normal counterpart were measured. Functions of Cerk in ovarian cancer was examined.

MATERIALS, SETTING, METHODS: Immunohistochemistry, ELISA and mass spectrometry methods were used to measure the level of ceramids, C1P and CerK in primary tissues. Proliferation and apoptosis assays were performed in ovarian cancer cells after CERK depletion, CERK overexpression and NVP-231 treatment in the absence or presence of cisplatin.

RESULTS: Compared to normal ovarian cells, CerK and its-mediated bioactive sphingolipids ceramide and ceramide 1-phosphate (C1P) were decreased in ovarian cancer tissues. Interestingly, cisplatin-resistant ovarian cancer cells displayed increased CerK, decreased ceramide and increased C1P, and furthermore that CerK level was closely associated with ceramide and C1P levels in ovarian cancer cells. Functional analysis demonstrated that CerK overexpression was sufficient to promote growth and confer chemo-resistance in ovarian cancer cells. CerK inhibition via both genetic and pharmacological approaches suppressed growth and induced apoptosis in cisplatin-resistant cells, and furthermore that significantly augmented cisplatin's efficacy.

LIMITATIONS: The functional analysis of C1P was performed in in vitro ovarian cancer cells. In vivo studies were needed to further confirm the effects of CERK inhibition.

CONCLUSIONS: Our work is the first to show the critical role of CerK as the underlying mechanism of ovarian cancer chemoresistance, through regulating ceramide and C1P.