Vitamin D3 enhances the response to cisplatin in bladder cancer through VDR and TAp73 signaling crosstalk
Abstract Background Vitamin D3 (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 deficie...
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doaj-22ca1c97f38345faa050654f631ae09d2020-11-25T01:56:26ZengWileyCancer Medicine2045-76342019-05-01852449246110.1002/cam4.2119Vitamin D3 enhances the response to cisplatin in bladder cancer through VDR and TAp73 signaling crosstalkBrittany L. Bunch0Yingyu Ma1Kristopher Attwood2Lauren Amable3Wei Luo4Carl Morrison5Khurshid A. Guru6Anna Woloszynska‐Read7Pamela A. Hershberger8Donald L. Trump9Candace S. Johnson10Department of Pharmacology and Therapeutics Roswell Park Cancer Institute Buffalo New YorkDepartment of Pharmacology and Therapeutics Roswell Park Cancer Institute Buffalo New YorkDepartment of Biostatistics and Bioinformatics Roswell Park Cancer Institute Buffalo New YorkNational Institute on Minority Health and Health Disparities National Institutes of Health Bethesda MarylandDepartment of Pharmacology and Therapeutics Roswell Park Cancer Institute Buffalo New YorkDepartment of Pathology Roswell Park Cancer Institute Buffalo New YorkDepartment of Urology Roswell Park Cancer Institute Buffalo New YorkDepartment of Pharmacology and Therapeutics Roswell Park Cancer Institute Buffalo New YorkDepartment of Pharmacology and Therapeutics Roswell Park Cancer Institute Buffalo New YorkInova Schar Cancer Institute Falls Church VirginiaDepartment of Pharmacology and Therapeutics Roswell Park Cancer Institute Buffalo New YorkAbstract Background Vitamin D3 (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 D3 (1,25D3). Lastly, using BCa cell lines, T24 and RT‐112, the mechanism of action of 1,25D3 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 D3 (25D3) levels was significantly associated with worse response to cisplatin. Pretreating deficient mice with 1,25D3, reduced tumor volume compared to cisplatin monotherapy. In vitro, 1,25D3 pretreatment increased the apoptotic response to cisplatin. 1,25D3 pretreatment increased expression of TAp73 and its pro‐apoptotic targets, in a VDR dependent manner. VDR and its transcriptional targets were induced after 1,25D3 treatment and further increased after the combination of 1,25D3 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.https://doi.org/10.1002/cam4.2119bladder cancercisplatinTAp73VDRvitamin D3 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Brittany L. Bunch Yingyu Ma Kristopher Attwood Lauren Amable Wei Luo Carl Morrison Khurshid A. Guru Anna Woloszynska‐Read Pamela A. Hershberger Donald L. Trump Candace S. Johnson |
spellingShingle |
Brittany L. Bunch Yingyu Ma Kristopher Attwood Lauren Amable Wei Luo Carl Morrison Khurshid A. Guru Anna Woloszynska‐Read Pamela A. Hershberger Donald L. Trump Candace S. Johnson Vitamin D3 enhances the response to cisplatin in bladder cancer through VDR and TAp73 signaling crosstalk Cancer Medicine bladder cancer cisplatin TAp73 VDR vitamin D3 |
author_facet |
Brittany L. Bunch Yingyu Ma Kristopher Attwood Lauren Amable Wei Luo Carl Morrison Khurshid A. Guru Anna Woloszynska‐Read Pamela A. Hershberger Donald L. Trump Candace S. Johnson |
author_sort |
Brittany L. Bunch |
title |
Vitamin D3 enhances the response to cisplatin in bladder cancer through VDR and TAp73 signaling crosstalk |
title_short |
Vitamin D3 enhances the response to cisplatin in bladder cancer through VDR and TAp73 signaling crosstalk |
title_full |
Vitamin D3 enhances the response to cisplatin in bladder cancer through VDR and TAp73 signaling crosstalk |
title_fullStr |
Vitamin D3 enhances the response to cisplatin in bladder cancer through VDR and TAp73 signaling crosstalk |
title_full_unstemmed |
Vitamin D3 enhances the response to cisplatin in bladder cancer through VDR and TAp73 signaling crosstalk |
title_sort |
vitamin d3 enhances the response to cisplatin in bladder cancer through vdr and tap73 signaling crosstalk |
publisher |
Wiley |
series |
Cancer Medicine |
issn |
2045-7634 |
publishDate |
2019-05-01 |
description |
Abstract Background Vitamin D3 (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 D3 (1,25D3). Lastly, using BCa cell lines, T24 and RT‐112, the mechanism of action of 1,25D3 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 D3 (25D3) levels was significantly associated with worse response to cisplatin. Pretreating deficient mice with 1,25D3, reduced tumor volume compared to cisplatin monotherapy. In vitro, 1,25D3 pretreatment increased the apoptotic response to cisplatin. 1,25D3 pretreatment increased expression of TAp73 and its pro‐apoptotic targets, in a VDR dependent manner. VDR and its transcriptional targets were induced after 1,25D3 treatment and further increased after the combination of 1,25D3 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. |
topic |
bladder cancer cisplatin TAp73 VDR vitamin D3 |
url |
https://doi.org/10.1002/cam4.2119 |
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