Activation of Vitamin D/VDR Signaling Reverses Gemcitabine Resistance of Pancreatic Cancer Cells Through Inhibition of MUC1 Expression

• DOI: 10.1007/s10620-023-07931-3
• Publication Date: 2023-04-18T09:03:06Z
• Authors: Daoyan Wei; Liang Wang; Yi Liu; Margarete A. Hafley; Lin Tan; Philip L. Lorenzi; Peiying Yang; Xiangsheng Zuo; Robert S. Bresalier
• Keywords: MUC1; Paricalcitol

Abstract Background Pancreatic ductal adenocarcinoma (PDA) has a poor prognosis largely due to its therapeutic resistance. Inactivation of vitamin D/vitamin D receptor (VDR) signaling contributes to the malignant phenotype of PDA, and altered expression of oncoprotein mucin 1 (MUC1) is involved in drug resistance of cancer cells. In the present study, we determined whether vitamin D/VDR signaling regulates the expression and function of MUC1 and its effect on gemcitabine resistance of pancreatic cancer cells. Methods We performed an unbiased reverse-phase protein array (RPPA) to identify vitamin D3 downstream molecules in PDA cells. We used molecular analyses and animal models to determine the impact of vitamin D/VDR signaling on MUC1 expression and response to gemcitabine treatment. Results RPPA analysis indicated that MUC1 protein expression was significantly reduced in human PDA cells after treatment with vitamin D3 or its analog calcipotriol. VDR negatively regulated MUC1 expression in both gain- and loss-of-function assays. Vitamin D3 or its analog significantly induced VDR and inhibited MUC1 expression in AsPC1-GemR and Colo357-GemR gemcitabine-resistant cells and sensitized the resistant cells to gemcitabine treatment. siRNA knockdown experiments indicated that inhibition of MUC1 expression was essential for calcipotriol-associated sensitization of PDA cells to gemcitabine treatment in vitro. Administration of the vitamin D3 analog paricalcitol significantly enhanced the therapeutic efficacy of gemcitabine in xenograft and orthotopic mouse models and increased the intratumoral concentration of dFdCTP, the active gemcitabine metabolite. Conclusions These 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.