Oncotarget

Research Papers:

1 alpha, 25-dihydroxylvitamin D3 promotes Bacillus Calmette-Guérin immunotherapy of bladder cancer

Jong-Wei Hsu, Peng-Nien Yin, Ronald Wood _, James Messing, Edward Messing and Yi-Fen Lee

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Oncotarget. 2013; 4:2397-2406. https://doi.org/10.18632/oncotarget.1494

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Abstract

Jong-Wei Hsu1,2, Peng-Nien Yin1, Ronald Wood3, James Messing4, Edward Messing1, and Yi-Fen Lee1,2

1 Department of Urology, University of Rochester, Rochester, New York, USA

2 Department of Pathology, University of Rochester, Rochester, New York, USA

3 Department of Obstetrics and Gynecology, University of Rochester, Rochester, New York, USA

4 Cornell University, Ithaca, New York USA

Correspondence:

Yi-Fen Lee, email:

Keywords: vitamin D, Bacillus Calmette-Guérin, bladder cancer, immunotherapy, interleukin 8

Received: October 14, 2013 Accepted: November 17, 2013 Published: November 19, 2013

Abstract

Bacillus Calmette-Guérin (BCG), a vaccine against tuberculosis(TB), has been used and proven to be one of the most effective treatments for non-muscle invasive bladder cancer (BCa). However, the mechanisms of BCG action have not been completely understood, thereby limiting the improvement of BCG therapy. Vitamin D deficiency has been associated with a high risk of TB infection, and the beneficial effect of UV exposure in TB patients was proven to be mediated via activation of vitamin D signals of innate immune cells. Thus, vitamin D signals might be involved in mediating BCG immunotherapy. To test this hypothesis, we examined the impact of 1alpha, 25-dihydroxyvitamin D3 (1,25-VD) on BCG-induced response in BCa cells and macrophage cells. Our data revealed that 1,25-VD promotes BCG-induced interleukin 8 (IL-8) secretion by BCa cells, consequently inducing the migration of macrophage, THP-1. This THP-1 cell migration promoted by 1,25-VD can be blocked by IL-8 neutralized antibody. Furthermore, 1,25-VD increased BCG-induced expression of macrophage markers in THP-1 cell, and enhanced the BCG-induced THP-1 cytotoxicity against low-grade BCa cells. Importantly, a pre-clinical trial using the N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN)-induced BCa mouse model revealed that intravesical co-treatment of 1,25-VD with BCG can prolong mice survival. These data demonstrate a novel mechanism by which 1,25-VD promotes BCG-mediated anti-BCa pathways and provides a platform for improving BCG efficacy with combination of 1,25-VD.


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