维生素 D 通过 VDR 和 TAp73 信号转导相互作用增强膀胱癌对顺铂的反应。
Vitamin D enhances the response to cisplatin in bladder cancer through VDR and TAp73 signaling crosstalk.
机构信息
Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, New York.
Department of Biostatistics and Bioinformatics, Roswell Park Cancer Institute, Buffalo, New York.
出版信息
Cancer Med. 2019 May;8(5):2449-2461. doi: 10.1002/cam4.2119. Epub 2019 Apr 10.
BACKGROUND
Vitamin D (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 (1,25D ). Lastly, using BCa cell lines, T24 and RT-112, the mechanism of action of 1,25D 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 (25D ) levels was significantly associated with worse response to cisplatin. Pretreating deficient mice with 1,25D , reduced tumor volume compared to cisplatin monotherapy. In vitro, 1,25D pretreatment increased the apoptotic response to cisplatin. 1,25D 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 treatment and further increased after the combination of 1,25D 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.
背景
维生素 D（VitD）缺乏与膀胱癌（BCa）的发病率增加和生存预后恶化有关。除了膀胱切除术外，患者还接受基于顺铂的化疗，但 30%-50%的患者并未从中受益。VitD 缺乏对化疗反应的影响尚不清楚。
方法
为了测试 VitD 补充对顺铂反应的影响，我们分析了患者的血清 VitD 水平，并将其与生存相关联。在体内，用 VitD 缺乏的小鼠进行顺铂治疗，并用或不用活性 VitD 代谢物 1,25-二羟维生素 D（1,25D）预处理。最后，使用 BCa 细胞系 T24 和 RT-112，通过凋亡测定、Western blot 和 RT-PCR 确定 1,25D 和顺铂联合治疗的作用机制。
结果
在这项研究中，我们确定低血清 25-羟维生素 D（25D）水平与对顺铂的反应较差显著相关。用 1,25D 预处理缺乏症小鼠可减少肿瘤体积，与顺铂单药治疗相比。在体外，1,25D 预处理增加了对顺铂的促凋亡反应。1,25D 预处理以 VDR 依赖性方式增加 TAp73 及其促凋亡靶标的表达。1,25D 处理后诱导 VDR 及其转录靶标表达，并用 1,25D 和顺铂联合处理后进一步增加，以 TAp73 依赖性方式。
结论
我们的数据表明，VitD 缺乏可能是顺铂反应不良的生物标志物，用 VitD 预处理可以通过 VDR 和 TAp73 信号转导相互作用增加对顺铂的促凋亡反应。
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