Nuclear factor-kappaB sensitizes to benzyl isothiocyanate-induced antiproliferation in p53-deficient colorectal cancer cells

Research output: Contribution to journalArticle

18 Citations (Scopus)

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-K-B (NF-K-B) 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-K-B 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 k-B kinase, k-B-a and p65, the degradation of IK-B-CC, the translocation of p65 to the nucleus and the upregulation of NF-K-B 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-K-B pathway in p53-deficient colorectal cancer cells.

Original languageEnglish
Article numbere1534
JournalCell Death and Disease
Volume5
Issue number11
DOIs
Publication statusPublished - Jan 1 2014

Fingerprint

Colorectal Neoplasms
Catenins
Cyclin D1
HCT116 Cells
HT29 Cells
Small Interfering RNA
APC Genes
Tumor Suppressor Protein p53
benzyl isothiocyanate
Mutation
Vegetables
Phosphotransferases
Up-Regulation
Phosphorylation
3'-(1-butylphosphoryl)adenosine

ASJC Scopus subject areas

  • Cell Biology
  • Immunology
  • Cancer Research
  • Cellular and Molecular Neuroscience

Cite this

@article{6e3f2e234d634830894aedddc06a98de,
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-K-B (NF-K-B) 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-K-B 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 k-B kinase, k-B-a and p65, the degradation of IK-B-CC, the translocation of p65 to the nucleus and the upregulation of NF-K-B 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-K-B pathway in p53-deficient colorectal cancer cells.",
author = "N. Abe and Hou, {D. X.} and Shintaro Munemasa and Yoshiyuki Murata and Yoshimasa Nakamura",
year = "2014",
month = "1",
day = "1",
doi = "10.1038/cddis.2014.495",
language = "English",
volume = "5",
journal = "Cell Death and Disease",
issn = "2041-4889",
publisher = "Nature Publishing Group",
number = "11",

}

TY - JOUR

T1 - Nuclear factor-kappaB sensitizes to benzyl isothiocyanate-induced antiproliferation in p53-deficient colorectal cancer cells

AU - Abe, N.

AU - Hou, D. X.

AU - Munemasa, Shintaro

AU - Murata, Yoshiyuki

AU - Nakamura, Yoshimasa

PY - 2014/1/1

Y1 - 2014/1/1

N2 - 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-K-B (NF-K-B) 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-K-B 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 k-B kinase, k-B-a and p65, the degradation of IK-B-CC, the translocation of p65 to the nucleus and the upregulation of NF-K-B 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-K-B pathway in p53-deficient colorectal cancer cells.

AB - 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-K-B (NF-K-B) 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-K-B 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 k-B kinase, k-B-a and p65, the degradation of IK-B-CC, the translocation of p65 to the nucleus and the upregulation of NF-K-B 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-K-B pathway in p53-deficient colorectal cancer cells.

UR - http://www.scopus.com/inward/record.url?scp=84924991492&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84924991492&partnerID=8YFLogxK

U2 - 10.1038/cddis.2014.495

DO - 10.1038/cddis.2014.495

M3 - Article

C2 - 25412312

AN - SCOPUS:84924991492

VL - 5

JO - Cell Death and Disease

JF - Cell Death and Disease

SN - 2041-4889

IS - 11

M1 - e1534

ER -