Identification of a novel blocker of IκBα kinase activation that enhances apoptosis and inhibits proliferation and invasion by suppressing nuclear factor-κB

Bokyung Sung, Manoj K. Pandey, Yuki Nakajima, Hiroshi Nishida, Tetsuya Konishi, Madan M. Chaturvedi, Bharat B. Aggarwal

Research output: Contribution to journalArticlepeer-review

34 Scopus citations

Abstract

3,4-Dihydroxybenzalacetone (DBL) is a polyphenol derived from the medicinal plant Chaga [Inonotus obliquus (persoon) Pilat]. Although Chaga is usedin Russia folk medicine to treat tumors, very little is known about its mechanism of action. Because most genes involved in inflammation, antiapoptosis, and cell proliferation are regulated by the transcription factor nuclear factor-κB (NF-κB), we postulated that DBL activity is mediated via modulation of the NF-κB activation pathway. We investigated the effects of DBL on NF-κB activation by electrophoretic mobility shift assay and on NF-κB-regulated gene expression by Western blot analysis. We found that DBL suppressed NF-κB activation by a wide variety of inflammatory agents, including tumor necrosis factor (TNF), interleukin-1β, epidermal growth factor, okadaic acid, phorbol 12-myristate 13-acetate, and lipopolysaccharide. The suppression was not cell type specific and inhibited both inducible and constitutive NF-κB activation. DBL did not interfere with the binding of NF-κB to DNA but rather inhibited IκBα kinase activity, IκBα phosphorylation and degradation, p65 phosphorylation, and translocation. DBL also suppressed the expression of TNF-induced and NF-κB-regulated proliferative, antiapoptotic, and metastatic gene products. These effects correlated with enhancement of TNF-induced apoptosis and suppression of TNF-induced invasion. Together, our results indicate that DBL inhibits NF-κB activation and NF-κB-regulated gene expression, which may explain the ability of DBL to enhance apoptosis and inhibit invasion.

Original languageEnglish (US)
Pages (from-to)191-201
Number of pages11
JournalMolecular Cancer Therapeutics
Volume7
Issue number1
DOIs
StatePublished - Jan 1 2008
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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