title: Proteasome inhibitors induce inhibitory kappa B (I kappa B) kinase activation, I kappa B alpha degradation, and nuclear factor kappa B activation in HT-29 cells.
abstract: The transcription factor nuclear factor kappaB (NF-kappaB) is activated and seems to promote oncogenesis in certain cancers. A major mechanism of NF-kappaB activation in cells involves cytoplasm-to-nucleus translocation of this transcription factor after hydrolysis of the cytoplasmic inhibitor inhibitory kappaB (IkappaB) by the 26S proteasome. Because selective proteasome inhibitors have been shown to block IkappaB degradation; consequently, NF-kappaB activation in a variety of cellular systems, proteasome inhibitors were proposed as potential therapeutic agents for the treatment of cancer. However, under certain conditions, IkappaB degradation and NF-kappaB activation are not mediated by the proteasome system. We investigated how proteasome inhibitors affected NF-kappaB activation in the intestinal epithelial cancer cell line HT-29, which has been documented to have an atypical NF-kappaB 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-kappaB activation as indicated by both an increase in NF-kappaB DNA binding and transcriptional activity. This increase in NF-kappaB activation caused by proteasome inhibitors was accompanied by an increase in IkappaB kinase activation and a degradation of IkappaBalpha but not IkappaBbeta. Furthermore, proteasome inhibitors induced the expression of NF-kappaB target genes. In summary, these results demonstrate a unique effect of proteasome inhibitors on the IkappaB-NF-kappaB systems in HT-29 cells, in which proteasome inhibitors activate rather than deactivate the NF-kappaB system. We conclude that the use of proteasome inhibitors to block NF-kappaB activation in cancer cells may not always be a viable approach.
authors.affiliation: Department of Surgery, University of Medicine and Dentistry-New Jersey Medical School, Newark, New Jersey 07103, USA.
authors.forename: Zoltán H
authors.initials: ZH
authors.lastname: Németh
authors.forename: Hector R
authors.initials: HR
authors.lastname: Wong
authors.forename: Kelli
authors.initials: K
authors.lastname: Odoms
authors.forename: Edwin A
authors.initials: EA
authors.lastname: Deitch
authors.forename: Csaba
authors.initials: C
authors.lastname: Szabó
authors.forename: E Sylvester
authors.initials: ES
authors.lastname: Vizi
authors.forename: György
authors.initials: G
authors.lastname: Haskó
mesh_terms: D018938:Caco-2 Cells; D003546:Cysteine Endopeptidases / Q000378:metabolism; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D019073:HT29 Cells; D006801:Humans; D051550:I-kappa B Kinase; D007976:Leupeptins / Q000494:pharmacology; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D015853:Cysteine Proteinase Inhibitors; D007976:Leupeptins; D009097:Multienzyme Complexes; D016328:NF-kappa B; C089486:carbobenzoxy-leucyl-leucyl-norvalinal; D017346:Protein Serine-Threonine Kinases; C496559:CHUK protein, human; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C496565:IKBKE protein, human; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex