Activation of Vitamin D/VDR Signaling Reverses Gemcitabine Resistance of Pancreatic Cancer Cells Through Inhibition of MUC1 Expression.
Activation of Vitamin D/VDR Signaling Reverses Gemcitabine Resistance of Pancreatic Cancer Cells Through Inhibition of MUC1 Expression.
复制标题
维生素 D/VDR 信号的激活通过抑制 MUC1 表达来逆转胰腺癌细胞对吉西他滨的耐药性。
DOI：
10.1007/s10620-023-07931-3
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发表时间：
2023
影响因子：
3.1
通讯作者：
Bresalier,RobertS
中科院分区：
文献类型：
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作者：
Wei,Daoyan;Wang,Liang;Liu,Yi;Hafley,MargareteA;Tan,Lin;Lorenzi,PhilipL;Yang,Peiying;Zuo,Xiangsheng;Bresalier,RobertS
研究背景胰腺导管腺癌(PDA)因耐药，预后较差。维生素D/维生素D受体(VDR)信号失活可能参与了PDA的恶性表型，癌蛋白粘蛋白1(MUC1)的表达改变可能与肿瘤细胞耐药有关。目的探讨维生素D/VDR信号是否调节MUC1的表达和功能，以及对胰腺癌细胞获得性吉西他滨耐药的影响。方法采用分子分析和动物模型研究维生素D/VDR信号对人PDA细胞MUC1表达及吉西他滨治疗反应的影响。VDR在增益性和失效性分析中均调节MUC1的表达。维生素D3或钙泊三醇可显著诱导获得性吉西他滨耐药的PDA细胞VDR和抑制MUC1的表达，并使耐药细胞对吉西他滨治疗增敏，而抑制MUC1的siRNA与体外帕利西他滨相关的增敏PDA细胞有关。帕利西他滨可显著提高吉西他滨在异种移植和原位小鼠模型中的治疗效果，并增加吉西他滨的活性代谢物dFdCTP的瘤内浓度。结论这些发现证实了先前未知的维生素D/VDR-MUC1信号轴参与了PDA对吉西他滨耐药性的调节，提示包括靶向激活维生素D/VDR信号转导在内的联合治疗可能会改善PDA患者的预后。
BackgroundPancreatic ductal adenocarcinoma (PDA) has a poor prognosis due to its therapeutic resistance. Inactivation of vitamin D/vitamin D receptor (VDR) signaling may contribute to the malignant phenotype of PDA and altered expression of oncoprotein mucin 1 (MUC1) may be involved in drug resistance of cancer cells.AimTo determine whether vitamin D/VDR signaling regulates the expression and function of MUC1 and its effect on acquired gemcitabine resistance of pancreatic cancer cells.MethodsMolecular analyses and animal models were used to determine the impact of vitamin D/VDR signaling on MUC1 expression and response to gemcitabine treatment.ResultsRPPA analysis indicated that MUC1 protein expression was significantly reduced in human PDA cells after treatment with vitamin D3 or its analog calcipotriol. VDR regulated MUC1 expression in both gain- and loss-of-function assays. Vitamin D3 or calcipotriol significantly induced VDR and inhibited MUC1 expression in acquired gemcitabine-resistant PDA cells and sensitized the resistant cells to gemcitabine treatment, while siRNA inhibition of MUC1 was associated with paricalcitol-associated sensitization of PDA cells to gemcitabine treatment in vitro. Administration of paricalcitol significantly enhanced the therapeutic efficacy of gemcitabine in xenograft and orthotopic mouse models and increased the intratumoral concentration of dFdCTP, the active metabolite of gemcitabine.ConclusionThese findings demonstrate a previously unidentified vitamin D/VDR-MUC1 signaling axis involved in the regulation of gemcitabine resistance in PDA and suggests that combinational therapies that include targeted activation of vitamin D/VDR signaling may improve the outcomes of patients with PDA.