Vitamin D 3 enhances the response to cisplatin in bladder cancer through VDR and TAp73 signaling crosstalk.

Background: Vitamin D ₃ (VitD) deficiency is linked to increased incidence and worse survival in bladder cancer (BCa). In addition to cystectomy, patients are treated with cisplatin-based chemotherapy, however 30%-50% of patients do not benefit from this treatment. The effects of VitD deficiency on response to chemotherapy remain unknown.
Methods: To test effects of VitD supplementation on the response to cisplatin we analyzed patient serum VitD levels and correlated that with survival. In vivo, VitD deficient mice were treated with cisplatin, with or without pretreatment with the active VitD metabolite, 1,25 dihydroxyvitamin D ₃ (1,25D ₃ ). Lastly, using BCa cell lines, T24 and RT-112, the mechanism of action of 1,25D ₃ and cisplatin combination treatment was determined by apoptosis assays, as well as western blot and RT-PCR.
Results: In this study, we determined that low serum 25 hydroxyvitamin D ₃ (25D ₃ ) levels was significantly associated with worse response to cisplatin. Pretreating deficient mice with 1,25D ₃ , reduced tumor volume compared to cisplatin monotherapy. In vitro, 1,25D ₃ pretreatment increased the apoptotic response to cisplatin. 1,25D ₃ pretreatment increased expression of TAp73 and its pro-apoptotic targets, in a VDR dependent manner. VDR and its transcriptional targets were induced after 1,25D ₃ treatment and further increased after the combination of 1,25D ₃ and cisplatin in a TAp73 dependent manner.
Conclusions: Our data suggest that VitD deficiency could be a biomarker for poor response to cisplatin, and pretreating with VitD can increase the apoptotic response to cisplatin through VDR and TAp73 signaling crosstalk.
(© 2019 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)