Proteasome Inhibitors Induce Inhibitory κB (IκB) Kinase Activation, IκBα Degradation, and Nuclear Factor κB Activation in HT-29 Cells

Zoltán H. Németh, Hector R. Wong, Kelli Odoms, Edwin A. Deitch, Csaba Szabó, E. Sylvester Vizi, György Haskó

    Research output: Contribution to journalArticle

    39 Scopus citations

    Abstract

    The transcription factor nuclear factor κB (NF-κB) is activated and seems to promote oncogenesis in certain cancers. A major mechanism of NF-κB activation in cells involves cytoplasm-to-nucleus translocation of this transcription factor after hydrolysis of the cytoplasmic inhibitor inhibitory κB (IκB) by the 26S proteasome. Because selective proteasome inhibitors have been shown to block IκB degradation; consequently, NF-κB activation in a variety of cellular systems, proteasome inhibitors were proposed as potential therapeutic agents for the treatment of cancer. However, under certain conditions, IκB degradation and NF-κB activation are not mediated by the proteasome system. We investigated how proteasome inhibitors affected NF-κB activation in the intestinal epithelial cancer cell line HT-29, which has been documented to have an atypical NF-κB regulation. Treatment of cells with the selective proteasome inhibitors carbobenzoxy-L-leucyl-L-leucyl-L-norvalinal (MG-115), carbobenzoxy-L-leucyl-L-leucyl-L-leucinal (MG-132), or lactacystin induced NF-κB activation as indicated by both an increase in NF-κB DNA binding and transcriptional activity. This increase in NF-κB activation caused by proteasome inhibitors was accompanied by an increase in IκB kinase activation and a degradation of IκBα but not IκBβ. Furthermore, proteasome inhibitors induced the expression of NF-κB target genes. In summary, these results demonstrate a unique effect of proteasome inhibitors on the IκB-NF-κB systems in HT-29 cells, in which proteasome inhibitors activate rather than deactivate the NF-κB system. We conclude that the use of proteasome inhibitors to block NF-κB activation in cancer cells may not always be a viable approach.

    Original languageEnglish (US)
    Pages (from-to)342-349
    Number of pages8
    JournalMolecular pharmacology
    Volume65
    Issue number2
    DOIs
    StatePublished - Feb 2004

    ASJC Scopus subject areas

    • Molecular Medicine
    • Pharmacology

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