Open AccessVitamin D 3 enhances the response to cisplatin in bladder cancer through VDR and TA p73 signaling crosstalk
Author(s) -
Bunch Brittany L.,
Ma Yingyu,
Attwood Kristopher,
Amable Lauren,
Luo Wei,
Morrison Carl,
Guru Khurshid A.,
WoloszynskaRead Anna,
Hershberger Pamela A.,
Trump Donald L.,
Johnson Candace S.
Publication year - 2019
Publication title -
cancer medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.403
H-Index - 53
ISSN - 2045-7634
DOI - 10.1002/cam4.2119
Subject(s) - cisplatin , calcitriol receptor , apoptosis , in vivo , bladder cancer , medicine , chemotherapy , cancer research , western blot , endocrinology , vitamin d and neurology , pharmacology , cancer , oncology , chemistry , biology , biochemistry , microbiology and biotechnology , gene
Background Vitamin D 3 (VitD) deficiency is linked to increased incidence and worse survival in bladder cancer ( BC a). 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 BC a 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 TA p73 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 TA p73 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 TA p73 signaling crosstalk.