RRC ID 45372
Author Abe N, Hou DX, Munemasa S, Murata Y, Nakamura Y.
Title Nuclear factor-kappaB sensitizes to benzyl isothiocyanate-induced antiproliferation in p53-deficient colorectal cancer cells.
Journal Cell Death Dis
Abstract Benzyl isothiocyanate (BITC), a dietary isothiocyanate derived from cruciferous vegetables, inhibits the proliferation of colorectal cancer cells, most of which overexpress β-catenin as a result of mutations in the genes for adenomatous polyposis coli or mutations in β-catenin itself. Because nuclear factor-κB (NF-κB) is a plausible target of BITC signaling in inflammatory cell models, we hypothesized that it is also involved in BITC-inhibited proliferation of colorectal cancer cells. siRNA-mediated knockdown of the NF-κB p65 subunit significantly decreased the BITC sensitivity of human colorectal cancer HT-29 cells with mutated p53 tumor suppressor protein. Treating HT-29 cells with BITC induced the phosphorylation of IκB kinase, IκB-α and p65, the degradation of IκB-α, the translocation of p65 to the nucleus and the upregulation of NF-κB transcriptional activity. BITC also decreased β-catenin binding to a positive cis element of the cyclin D1 promoter and thus inhibited β-catenin-dependent cyclin D1 transcription, possibly through a direct interaction between p65 and β-catenin. siRNA-mediated knockdown of p65 confirmed that p65 negatively affects cyclin D1 expression. On the other hand, when human colorectal cancer HCT-116 cells with wild-type p53 were treated with BITC, translocation of p65 to the nucleus was inhibited rather than enhanced. p53 knockout increased the BITC sensitivity of HCT-116 cells in a p65-dependent manner, suggesting that p53 negatively regulates p65-dependent effects. Together, these results identify BITC as a novel type of antiproliferative agent that regulates the NF-κB pathway in p53-deficient colorectal cancer cells.
Volume 5
Pages e1534
Published 2014-11-20
DOI 10.1038/cddis.2014.495
PII cddis2014495
PMID 25412312
PMC PMC4260753
MeSH Antineoplastic Agents, Phytogenic / pharmacology* Apoptosis / drug effects Cell Proliferation / drug effects Cyclin D1 / genetics Cyclin D1 / metabolism Gene Expression Regulation, Neoplastic* HCT116 Cells HT29 Cells Humans I-kappa B Kinase / genetics I-kappa B Kinase / metabolism Isothiocyanates / pharmacology* Phosphorylation / drug effects Promoter Regions, Genetic Protein Transport / drug effects RNA, Small Interfering / genetics RNA, Small Interfering / metabolism Signal Transduction Transcription Factor RelA / genetics* Transcription Factor RelA / metabolism Tumor Suppressor Protein p53 / antagonists & inhibitors Tumor Suppressor Protein p53 / genetics* Tumor Suppressor Protein p53 / metabolism beta Catenin / genetics beta Catenin / metabolism
IF 5.638
Times Cited 6
WOS Category CELL BIOLOGY
Resource
Human and Animal Cells