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 ?-catenin as a result of mutations in the genes for adenomatous polyposis coli or mutations in ?-catenin itself. Because nuclear factor-?B (NF-?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-?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 I?B kinase, I?B-? and p65, the degradation of I?B-?, the translocation of p65 to the nucleus and the upregulation of NF-?B transcriptional activity. BITC also decreased ?-catenin binding to a positive cis element of the cyclin D1 promoter and thus inhibited ?-catenin-dependent cyclin D1 transcription, possibly through a direct interaction between p65 and ?-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-?B pathway in p53-deficient colorectal cancer cells.

SUBMITTER: Abe N 

PROVIDER: S-EPMC4260753 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature