QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Németh, Z. H. Articles by Haskó, G. Search for Related Content PubMed PubMed Citation Articles by Németh, Z. H. Articles by Haskó, G.

Proteasome Inhibitors Induce Inhibitory B (IB) Kinase Activation, IB Degradation, and Nuclear Factor B Activation in HT-29 Cells

Department of Surgery, University of Medicine and Dentistry of New Jersey-New Jersey Medical School, Newark, New Jersey (Z.H.N., E.A.D., C.S., G.H.); Division of Critical Care Medicine, Children's Hospital Medical Center and Children's Hospital Research Foundation, Cincinnati, Ohio (H.R.W., K.O.); and Department of Pharmacology, Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary (E.S.V., G.H.)

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

Address correspondence to: Dr. György Haskó, Department of Surgery, UMD-New Jersey Medical School, 185 South Orange Avenue, University Heights, Newark, NJ 07103. E-mail: haskoge{at}umdnj.edu

This article has been cited by other articles:

				H.-Q. Wang, Z.-X. Du, H.-Y. Zhang, and D.-X. Gao Different Induction of GRP78 and CHOP as a Predictor of Sensitivity to Proteasome Inhibitors in Thyroid Cancer Cells Endocrinology, July 1, 2007; 148(7): 3258 - 3270. [Abstract] [Full Text] [PDF]

				S. Skvortsov, I. Skvortsova, T. Stasyk, N. Schiefermeier, A. Neher, A. R. Gunkel, G. K. Bonn, L. A. Huber, P. Lukas, C. M. Pleiman, et al. Antitumor activity of CTFB, a novel anticancer agent, is associated with the down-regulation of nuclear factor-{kappa}B expression and proteasome activation in head and neck squamous carcinoma cell lines Mol. Cancer Ther., June 1, 2007; 6(6): 1898 - 1908. [Abstract] [Full Text] [PDF]

				K. A. Park, H. S. Byun, M. Won, K.-J. Yang, S. Shin, L. Piao, J. M. Kim, W.-H. Yoon, E. Junn, J. Park, et al. Sustained activation of protein kinase C downregulates nuclear factor-{kappa}B signaling by dissociation of IKK-{gamma} and Hsp90 complex in human colonic epithelial cells Carcinogenesis, January 1, 2007; 28(1): 71 - 80. [Abstract] [Full Text] [PDF]

				X. Dolcet, D. Llobet, M. Encinas, J. Pallares, A. Cabero, J. A. Schoenenberger, J. X. Comella, and X. Matias-Guiu Proteasome Inhibitors Induce Death but Activate NF-{kappa}B on Endometrial Carcinoma Cell Lines and Primary Culture Explants J. Biol. Chem., August 4, 2006; 281(31): 22118 - 22130. [Abstract] [Full Text] [PDF]

				C. Taille, J. El-Benna, S. Lanone, M.-C. Dang, E. Ogier-Denis, M. Aubier, and J. Boczkowski Induction of Heme Oxygenase-1 Inhibits NAD(P)H Oxidase Activity by Down-regulating Cytochrome b558 Expression via the Reduction of Heme Availability J. Biol. Chem., July 2, 2004; 279(27): 28681 - 28688. [Abstract] [Full Text] [PDF]