title: Nuclear factor-kappaB sensitizes to benzyl isothiocyanate-induced antiproliferation in p53-deficient colorectal cancer cells.
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.
authors.affiliation: 1] Graduate School of Environmental and Life Science, Okayama University, Okayama, Japan [2] Japan Society for the Promotion of Science, Tokyo, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Abe
authors.affiliation: Department of Biochemical Science and Technology, Faculty of Agriculture, Kagoshima University, Korimoto, Japan.
authors.forename: D-X
authors.initials: DX
authors.lastname: Hou
authors.affiliation: Graduate School of Environmental and Life Science, Okayama University, Okayama, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Munemasa
authors.affiliation: Graduate School of Environmental and Life Science, Okayama University, Okayama, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Murata
authors.affiliation: Graduate School of Environmental and Life Science, Okayama University, Okayama, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Nakamura
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics / Q000378:metabolism; D017879:Isothiocyanates / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D011401:Promoter Regions, Genetic; D021381:Protein Transport / Q000187:drug effects; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D051996:Transcription Factor RelA / Q000235:genetics* / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
chemical_list: D000972:Antineoplastic Agents, Phytogenic; C530104:CCND1 protein, human; C495270:CTNNB1 protein, human; D017879:Isothiocyanates; D034741:RNA, Small Interfering; D051996:Transcription Factor RelA; D016159:Tumor Suppressor Protein p53; D051176:beta Catenin; D019938:Cyclin D1; C031403:benzyl isothiocyanate; D051550:I-kappa B Kinase