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

Hsu JW, Yin PN, Wood R, Messing J, Messing E, Lee YF - Oncotarget (2013)

Bottom Line: 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.This THP-1 cell migration promoted by 1,25-VD can be blocked by IL-8 neutralized antibody.

View Article: PubMed Central - PubMed

Affiliation: Department of Urology, University of Rochester, Rochester, New York, USA.

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 1 alpha, 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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Detection of VDR expression in human bladder(A) VDR protein expression was detected in human bladder tissues including benign bladder and bladder carcinoma in situ (CIS) by IHC staining. (B) VDR expression in bladder cell lines, including immortalized normal urothelial cell line SV-HUC and three BCa cell lines, TCC-HUC (grade IV), HT1197 (low grade) and T24 (grade III) cells by Western blotting assay. β-actin was used as a loading control.
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Figure 1: Detection of VDR expression in human bladder(A) VDR protein expression was detected in human bladder tissues including benign bladder and bladder carcinoma in situ (CIS) by IHC staining. (B) VDR expression in bladder cell lines, including immortalized normal urothelial cell line SV-HUC and three BCa cell lines, TCC-HUC (grade IV), HT1197 (low grade) and T24 (grade III) cells by Western blotting assay. β-actin was used as a loading control.

Mentions: To understand if vitamin D signaling occurs in the human bladder, the expression and distribution of vitamin D receptor (VDR)-- the key factor that modulates vitamin D activity-- were examined in human bladder samples by immunohistochemistry (IHC) staining. As shown in Fig. 1A, we successfully detected VDR expression in both normal human urothelium and carcinoma in situ (CIS) so as to suggest a potential vitamin D action in the human bladder. Moreover, we also detected VDR expression levels in various bladder cell lines, including immortalized normal urothelial cell line; SV-HUC; and two high grade BCa cell lines; T24 (grade III); TCC-SUP (grade IV) and one low grade HT1197 by Western blot analysis. VDR is expressed in all the cells we examined with higher abundance in HT1197 and T24 cells and much less expressed in SV-HUC cells (Fig. 1B).


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

Hsu JW, Yin PN, Wood R, Messing J, Messing E, Lee YF - Oncotarget (2013)

Detection of VDR expression in human bladder(A) VDR protein expression was detected in human bladder tissues including benign bladder and bladder carcinoma in situ (CIS) by IHC staining. (B) VDR expression in bladder cell lines, including immortalized normal urothelial cell line SV-HUC and three BCa cell lines, TCC-HUC (grade IV), HT1197 (low grade) and T24 (grade III) cells by Western blotting assay. β-actin was used as a loading control.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3926835&req=5

Figure 1: Detection of VDR expression in human bladder(A) VDR protein expression was detected in human bladder tissues including benign bladder and bladder carcinoma in situ (CIS) by IHC staining. (B) VDR expression in bladder cell lines, including immortalized normal urothelial cell line SV-HUC and three BCa cell lines, TCC-HUC (grade IV), HT1197 (low grade) and T24 (grade III) cells by Western blotting assay. β-actin was used as a loading control.
Mentions: To understand if vitamin D signaling occurs in the human bladder, the expression and distribution of vitamin D receptor (VDR)-- the key factor that modulates vitamin D activity-- were examined in human bladder samples by immunohistochemistry (IHC) staining. As shown in Fig. 1A, we successfully detected VDR expression in both normal human urothelium and carcinoma in situ (CIS) so as to suggest a potential vitamin D action in the human bladder. Moreover, we also detected VDR expression levels in various bladder cell lines, including immortalized normal urothelial cell line; SV-HUC; and two high grade BCa cell lines; T24 (grade III); TCC-SUP (grade IV) and one low grade HT1197 by Western blot analysis. VDR is expressed in all the cells we examined with higher abundance in HT1197 and T24 cells and much less expressed in SV-HUC cells (Fig. 1B).

Bottom Line: 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.This THP-1 cell migration promoted by 1,25-VD can be blocked by IL-8 neutralized antibody.

View Article: PubMed Central - PubMed

Affiliation: Department of Urology, University of Rochester, Rochester, New York, USA.

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 1 alpha, 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.

Show MeSH
Related in: MedlinePlus