Bortezomib induces canonical nuclear factor-κB activation in multiple myeloma cells

Teru Hideshima, Hiroshi Ikeda, Dharminder Chauhan, Yutaka Okawa, Noopur Raje, Klaus Podar, Constantine Mitsiades, Nikhil C Munshi, Paul G Richardson, Ruben D Carrasco, Kenneth C Anderson

Research output: Journal article (peer-reviewed)Journal article

317 Citations (Scopus)

Abstract

Bortezomib is a proteasome inhibitor with remarkable preclinical and clinical antitumor activity in multiple myeloma (MM) patients. The initial rationale for its use in MM was inhibition of nuclear factor (NF)-κB activity by blocking proteasomal degradation of inhibitor of κBα (IκBα). Bortezomib inhibits inducible NF-κB activity; however, its impact on constitutive NF-κB activity in MM cells has not yet been defined. In this study, we demonstrate that bortezomib significantly downregulated IκBα expression and triggered NF-κB activation in MM cell lines and primary tumor cells fromMMpatients. Importantly, no inhibition of p65 (RelA) nuclear translocation was recognized after bortezomib treatment in a murine xenograft model bearinghumanMMcells. Bortezomib-induced NF-κB activation was mediated via the canonical pathway. Moreover, other classes of proteasome inhibitors also induced IκBα down-regulation associated with NF-κB activation. Molecular mechanisms whereby bortezomib induced IκBα down-regulation were further examined. Bortezomib triggered phosphorylation of IκB kinase (IKKβ) and its upstream receptor-interacting protein 2, whereas IKKβ inhibitor MLN120B blocked bortezomib-induced IκBα down-regulation and NF-κB activation, indicating receptorinteracting protein 2/IKKβ signaling plays crucial role in bortezomib-induced NF-κB activation. Moreover, IKKβ inhibitors enhanced bortezomib-induced cytotoxicity. Our studies therefore suggest that bortezomib-induced cytotoxicity cannot be fully attributed to inhibition of canonical NF-κB activity in MM cells.

Original languageEnglish
Pages (from-to)1046-1052
Number of pages7
JournalBlood
Volume114
Issue number5
DOIs
Publication statusPublished - 30 Jul 2009
Externally publishedYes

Keywords

  • Animals
  • Antineoplastic Agents/pharmacology
  • Boronic Acids/pharmacology
  • Bortezomib
  • Down-Regulation/drug effects
  • Enzyme Activation/drug effects
  • Gene Expression Regulation, Neoplastic/drug effects
  • Humans
  • I-kappa B Kinase/antagonists & inhibitors
  • I-kappa B Proteins/metabolism
  • Mice
  • Mice, SCID
  • Multiple Myeloma/drug therapy
  • NF-KappaB Inhibitor alpha
  • NF-kappa B/drug effects
  • Neoplasm Proteins/drug effects
  • Phosphorylation
  • Protease Inhibitors/pharmacology
  • Protein Processing, Post-Translational/drug effects
  • Pyrazines/pharmacology
  • Receptor-Interacting Protein Serine-Threonine Kinase 2/metabolism
  • Tumor Cells, Cultured/drug effects
  • Xenograft Model Antitumor Assays

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

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