Dataset Information

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 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.

SUBMITTER: Bunch BL

PROVIDER: S-EPMC6537042 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Publications

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

Bunch Brittany L BL Ma Yingyu Y Attwood Kristopher K Amable Lauren L Luo Wei W Morrison Carl C Guru Khurshid A KA Woloszynska-Read Anna A Hershberger Pamela A PA Trump Donald L DL Johnson Candace S CS

Cancer medicine 20190410 5

<h4>Background</h4>Vitamin D<sub>3</sub> (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.<h4>Methods</h4>To test effects of VitD supplementation on the response to cisplatin we analyzed patient serum VitD levels and correlated that ...[more]

PMID: 30972950

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Project description:BackgroundCisplatin-based chemotherapy is mainstay treatment in urinary bladder cancer (UBC). However, tumor recurrence frequently occurs with the acquisition of cisplatin resistance. We explored the potential effect of a polyherbal preparation, Zyflamend, on UBC cells resistant to cisplatin treatment.MethodsTo establish a cisplatin-resistant human bladder cancer cell line, T24 cells were cultured in increasing concentrations of cisplatin for more than 10 months. These cells (T24R) were then treated with different concentrations of Zyflamend, and both proliferation and activity of nuclear factor kappaB (NFκB) signaling pathway were examined. To test the synergistic effect between Zyflamend and cisplatin, we treated T24R cells either with Zyflamend or cisplatin alone, or in combination. Apoptotic effect was evaluated by Annexin V/propidium iodide double staining, and the levels of the proteins involved in cell cycle and anti-apoptosis were examined by Western blotting. Finally, mice with palpable xenograft were treated either with cisplatin and Zyflamend alone or in combination for 28 days before they were sacrificed for measuring the sizes and weights of the tumor tissues. In addition, proliferation and apoptosis markers were examined by immunohistochemistry.ResultsComparing to that in the parental T24 cells, NFκB is constitutively active in cisplatin-resistant T24R cells. Zyflamend is capable of inhibiting the growth of T24, T24R, as well as another UBC cell line J82 in a concentration-dependent manner. Mechanistically, Zyflamend suppresses NFκB-mediated cell proliferation, survival, and invasion/angiogenesis and induces apoptosis. In addition, Zyflamend significantly increased the sensitivity of T24R and J82 cells to cisplatin treatment and these findings were confirmed in T24R xenograft model with reduced proliferation index and decreased expression of RelA and its downstream target MMP9.ConclusionZyflamend is capable of counteracting bladder cancer resistance to cisplatin by repressing proliferation and inducing apoptosis through targeting NFκB signaling pathway.

Dataset Information

Vitamin D₃ enhances the response to cisplatin in bladder cancer through VDR and TAp73 signaling crosstalk.

Background

Methods

Results

Conclusions

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

Vitamin D3 enhances the response to cisplatin in bladder cancer through VDR and TAp73 signaling crosstalk.

Background

Methods

Results

Conclusions

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Vitamin D₃ enhances the response to cisplatin in bladder cancer through VDR and TAp73 signaling crosstalk.