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Mol Cancer Ther. 2010 Jun;9(6):1596-608. doi: 10.1158/1535-7163.MCT-09-1146. Epub 2010 May 18.

Benzyl isothiocyanate-mediated inhibition of histone deacetylase leads to NF-kappaB turnoff in human pancreatic carcinoma cells.

Author information

1
Department of Biomedical Sciences, and Cancer Biology Center, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, Texas 79106, USA.

Abstract

NF-kappaB/p65 is constitutively activated in pancreatic cancers, where it plays a critical role in the transcriptional activation of multiple cell survival genes. We have previously shown the apoptosis-inducing effects of benzyl isothiocyanate (BITC) in pancreatic cancer cells. We hypothesized that inhibition of NF-kappaB/p65 could be the mechanism of BITC-induced apoptosis. Therefore, the effect of BITC on NF-kappaB/p65 was evaluated in BxPC-3, Capan-2, and normal HPDE-6 cells by Western blotting, transcriptional and DNA-binding activity, and immunohistochemistry in the xenografted tumors. Our results reveal a remarkable decrease in the phosphorylation of NF-kappaB/p65 at Ser(536) in both BxPC-3 and Capan-2 cells by BITC treatment. The expression of NF-kappaB/p65 was downregulated significantly in BxPC-3 cells, whereas it remained unchanged in Capan-2 cells. BITC treatment caused a significant decrease in NF-kappaB transcriptional and DNA-binding activity in both BxPC-3 and Capan-2 cells. A drastic decrease was observed in the expression and reporter activity of cyclin D1 in both the cell lines. Moreover, BITC also caused a significant decrease in the expression and activity of histone deacetylase (HDAC) 1 and HDAC3 in BxPC-3 and HDAC3 in Capan-2 cells. Overexpression of HDAC1 or HDAC3 abrogated the effects of BITC. BITC treatment did not cause any change in HDAC expression in normal HPDE-6 cells. Immunohistochemical analysis of tumors from BITC-treated mice showed significantly reduced staining for NF-kappaB, cyclin D1, HDAC1, and HDAC3 compared with control. Our results suggest inhibition of HDAC1/HDAC3 by BITC as a plausible mechanism of NF-kappaB inactivation, resulting in the in vitro and in vivo growth suppression of pancreatic cancer cells.

PMID:
20484017
PMCID:
PMC2946330
DOI:
10.1158/1535-7163.MCT-09-1146
[Indexed for MEDLINE]
Free PMC Article

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