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Molecular Pharmacology

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Research ArticleArticle

Dynamic Effect of Bortezomib on Nuclear Factor-κB Activity and Gene Expression in Tumor Cells

Myong-Hee Sung, Lorena Bagain, Zhong Chen, Tatiana Karpova, Xinping Yang, Christopher Silvin, Ty C. Voss, James G. McNally, Carter Van Waes and Gordon L. Hager
Molecular Pharmacology November 2008, 74 (5) 1215-1222; DOI: https://doi.org/10.1124/mol.108.049114
Myong-Hee Sung
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Lorena Bagain
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Zhong Chen
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Tatiana Karpova
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Xinping Yang
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Christopher Silvin
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Ty C. Voss
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James G. McNally
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Carter Van Waes
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Gordon L. Hager
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Abstract

Nuclear factor-κB (NF-κB) influences the initiation, progression, and maintenance of diverse cancer types. Despite current therapeutic efforts to block hyperactive NF-κB in cancer cells, the in vivo effects of a drug upon this complex pathway are unclear. We monitored NF-κB activity and a fast-expressing reporter level simultaneously in head and neck squamous carcinoma cells by quantitative live microscopy. The real-time single cell assay revealed the tumor necrosis factor-α-induced oscillation of NF-κB was echoed by equally dynamic reporter expression rate. Bortezomib is a proteasome inhibitor whose anticancer action is partly mediated through inhibition of NF-κB. When administered to preactivated cells, the drug gave rise to distinct inhibition dynamics, with discrete pulses of reporter induction remaining for hours. These findings suggest that, contrary to a simplistic presumption for a pathway “blockade,” the network dynamics and the intracellular pharmacokinetics of the inhibitor must be critically evaluated in developing strategies for optimal intervention of oncogenic pathways.

Footnotes

  • This work was supported by National Institute on Deafness and Other Communication Disorders intramural project Z01-DC-00016 and by the National Institutes of Health Intramural Research Program for Center for Cancer Research, National Cancer Institute. C.V.W. has received bortezomib and clinical trial support under a National Institutes of Health-approved Cooperative Research and Development Agreement with Millennium Pharmaceuticals.

  • ABBREVIATIONS: NF-κB, nuclear factor-κB; IκB, inhibitor of κB; IKK, IκB kinase; IL, interleukin; PS-341, [(1R)-3-methyl-1-[[(2S)-1-oxo-3-phenyl-2-[(pyrazinylcarbonyl)amino]propyl]amino]butyl] boronic acid; HNSCC, head and neck squamous cell carcinoma; TNF, tumor necrosis factor; EGFP, enhanced green fluorescent protein; EMEM, Eagle's minimal essential medium; DAPI, 4,6-diamidino-2-phenylindole; ex, excitation; em, emission; GFP, green fluorescent protein.

  • ↵ Embedded Image The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material.

    • Received May 24, 2008.
    • Accepted August 5, 2008.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 74 (5)
Molecular Pharmacology
Vol. 74, Issue 5
1 Nov 2008
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Research ArticleArticle

Dynamic Effect of Bortezomib on Nuclear Factor-κB Activity and Gene Expression in Tumor Cells

Myong-Hee Sung, Lorena Bagain, Zhong Chen, Tatiana Karpova, Xinping Yang, Christopher Silvin, Ty C. Voss, James G. McNally, Carter Van Waes and Gordon L. Hager
Molecular Pharmacology November 1, 2008, 74 (5) 1215-1222; DOI: https://doi.org/10.1124/mol.108.049114

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Research ArticleArticle

Dynamic Effect of Bortezomib on Nuclear Factor-κB Activity and Gene Expression in Tumor Cells

Myong-Hee Sung, Lorena Bagain, Zhong Chen, Tatiana Karpova, Xinping Yang, Christopher Silvin, Ty C. Voss, James G. McNally, Carter Van Waes and Gordon L. Hager
Molecular Pharmacology November 1, 2008, 74 (5) 1215-1222; DOI: https://doi.org/10.1124/mol.108.049114
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