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

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Abstract

Background

Pancreatic 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.

Aim

To determine whether vitamin D/VDR signaling regulates the expression and function of MUC1 and its effect on acquired gemcitabine resistance of pancreatic cancer cells.

Methods

Molecular analyses and animal models were used 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 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.

Conclusion

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.

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Data Availability

The raw protein RPPA data generated in this study are available in TCPA database under accession number #TCPA00000010 (with link: http://tcpaportal.org/tcpa/download/TCPA00000010.zip). Other data that support the findings of this study are available from the corresponding author upon request.

Abbreviations

MUC1:

Mucin 1

PDA:

Pancreatic ductal adenocarcinoma

PanIN:

Pancreatic intraepithelial neoplasia

VDR:

Vitamin D receptor

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Acknowledgments

This study made use of the MD Anderson Cancer Center Functional Proteomics RPPA Core Facility, the Metabolomics Core Facility, and Research Animal Support Facility, supported by Cancer Center Support Grant CA016672. We thank Dawn Chalaire, scientific editor in the Research Medical Library at MD Anderson Cancer Center, for editing the manuscript. The authors thank Wei Li for the graphic arts used in the manuscript.

Funding

The work was supported by the National Cancer Institute (R01 CA198090 to R.S.B), the NIH-funded Texas Medical Center Digestive Disease Center Research Core Center Program P30DK056338 (to R.S.B and D.W), and grants from the Elsa U. Pardee Foundation, the University of Texas MD Anderson Cancer Center Duncan Family Institute for Cancer Prevention and Risk Assessment, and the MD Anderson Cancer Center Institutional Research (to D.W).

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Authors and Affiliations

  1. Department of Gastroenterology, Hepatology, and Nutrition, Unit 1466, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX, 77030, USA

    Daoyan Wei, Liang Wang, Margarete A. Hafley & Robert S. Bresalier

  2. Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Yi Liu & Xiangsheng Zuo

  3. Metabolomics Core Facility, Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Lin Tan & Philip L. Lorenzi

  4. Department of Palliative, Rehabilitation and Integrative Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Peiying Yang

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  1. Daoyan Wei
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Contributions

DW and RB conceived the study, designed the experiments, and wrote the manuscript. DW, LW, YL, XZ, and MH performed various portions of animal experiments and histologic analysis and the in vitro experiments. YL performed part of the bioinformatic data analysis. PY, LT, and PLL helped with IC-MS assay and data analysis. XZ provided conceptual feedback for the manuscript. All authors have read and agreed to the publication of the manuscript. The work reported in the paper has been performed by the authors, unless clearly specified in the text.

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Correspondence to Robert S. Bresalier.

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The animal protocol and human subject protocol involved in this study were approved by the institutional Review Board of UT MD Anderson Cancer Center.

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Wei, D., Wang, L., Liu, Y. et al. Activation of Vitamin D/VDR Signaling Reverses Gemcitabine Resistance of Pancreatic Cancer Cells Through Inhibition of MUC1 Expression. Dig Dis Sci 68, 3043–3058 (2023). https://doi.org/10.1007/s10620-023-07931-3

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