SPHK1 contributes to cisplatin resistance in bladder cancer cells via the NONO/STAT3 axis

Sphingosine-1-phosphate (S1P) serves an important role in various physiological and pathophysiological processes, including the regulation of cell apoptosis, proliferation and survival. Sphingosine kinase 1 (SPHK1) is a lipid kinase that phosphorylates sphingosine to generate S1P. S1P has been proven to be positively correlated with chemotherapy resistance in breast cancer, colorectal carcinoma and non-small cell lung cancer. However, whether SPHK1 is involved in the development of cisplatin resistance remains to be elucidated. The present study aimed to identify the association between SPHK1 and chemoresistance in bladder cancer cells and to explore the therapeutic implications in patients with bladder cancer. Bladder cancer cell proliferation and apoptosis were determined using Cell Counting Kit-8 assays and flow cytometry, respectively. Apoptosis-related proteins were detected via western blotting. The results revealed that SPHK1 was positively correlated with cisplatin resistance in bladder cancer cells, exhibiting an antiapoptotic effect that was reflected by the downregulation of apoptosis-related proteins (Bax and cleaved caspase-3) and the upregulation of an antiapoptotic protein (Bcl-2) in SPHK1-overexpression cell lines. Suppression of SPHK1 by small interfering RNA or FTY-720 significantly reversed the antiapoptotic effect. A potential mechanism underlying SPHK1-induced cisplatin resistance and apoptosis inhibition may be activation of STAT3 via binding non-POU domain containing octamer binding. In conclusion, the present study suggested that SPHK1 displayed significant antiapoptotic effects in cisplatin-based treatment, thus may serve as a potential novel therapeutic target for the treatment for bladder cancer.