Vitamin D promotes apoptosis and enhances cisplatin sensitivity in bladder cancer cells by inhibiting the Warburg effect through the AKT/mTOR pathway

Abstract Objective Patients with bladder cancer (BCa) have a poor prognosis and are prone to metastasis. Deficiency of 1,25-dihydroxyvitamin D3 (VD) is associated with increased incidence and decreased survival in various tumors. Herein, we aimed to examine the effect of VD combined with cisplatin (DDP) on the proliferation and apoptosis of BCa cells and elucidate the underlying mechanism. Methods T24 and 5637 BCa cell lines were treated with different concentrations of DDP and VD to assess the effects of various doses of DDP and VD on BCa cytotoxicity and determine the appropriate combination dose. T24 cells were treated with DDP and VD to assess the effects of the drug combination on cell proliferation, apoptosis, cycling, Warburg effect, and DDP sensitivity. In addition, cells were treated with DDP, VD, pyruvic acid sodium (PAS), or SC79 to determine the effect of VD on the sensitivity of BCa cells to DDP mediated by inhibiting the Warburg effect through AKT/mTOR signaling. Results VD and DDP inhibited BCa cell proliferation; promoted apoptosis; downregulated the protein expression of GLUT1, LDHA, HK2, c-Myc, MRP1, and P-gp; and upregulated the expression of p-mTOR protein. VD combined with DDP reversed the effects of PAS on cells and promoted apoptosis by inhibiting the cellular Warburg effect. In addition, VD combined with DDP activated the AKT/mTOR pathway and reversed the effects of SC79 on cell proliferation and the Warburg effect. Conclusion VD could promote apoptosis and enhance DDP sensitivity in BCa cells by inhibiting the Warburg effect via the AKT/mTOR pathway.