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

Blood. 2009 Jul 30;114(5):1046-52. doi: 10.1182/blood-2009-01-199604. Epub 2009 May 12.

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)-kappaB activity by blocking proteasomal degradation of inhibitor of kappaBalpha (IkappaBalpha). Bortezomib inhibits inducible NF-kappaB activity; however, its impact on constitutive NF-kappaB activity in MM cells has not yet been defined. In this study, we demonstrate that bortezomib significantly down-regulated IkappaBalpha expression and triggered NF-kappaB activation in MM cell lines and primary tumor cells from MM patients. Importantly, no inhibition of p65 (RelA) nuclear translocation was recognized after bortezomib treatment in a murine xenograft model bearing human MM cells. Bortezomib-induced NF-kappaB activation was mediated via the canonical pathway. Moreover, other classes of proteasome inhibitors also induced IkappaBalpha down-regulation associated with NF-kappaB activation. Molecular mechanisms whereby bortezomib induced IkappaBalpha down-regulation were further examined. Bortezomib triggered phosphorylation of IkappaB kinase (IKKbeta) and its upstream receptor-interacting protein 2, whereas IKKbeta inhibitor MLN120B blocked bortezomib-induced IkappaBalpha down-regulation and NF-kappaB activation, indicating receptor-interacting protein 2/IKKbeta signaling plays crucial role in bortezomib-induced NF-kappaB activation. Moreover, IKKbeta inhibitors enhanced bortezomib-induced cytotoxicity. Our studies therefore suggest that bortezomib-induced cytotoxicity cannot be fully attributed to inhibition of canonical NF-kappaB activity in MM cells.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use
  • Boronic Acids / pharmacology*
  • Boronic Acids / therapeutic use
  • 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 Kinase / metabolism
  • I-kappa B Proteins / metabolism
  • Mice
  • Mice, SCID
  • Multiple Myeloma / drug therapy
  • Multiple Myeloma / genetics*
  • NF-KappaB Inhibitor alpha
  • NF-kappa B / drug effects*
  • NF-kappa B / physiology
  • Neoplasm Proteins / drug effects*
  • Neoplasm Proteins / physiology
  • Phosphorylation
  • Protease Inhibitors / pharmacology*
  • Protease Inhibitors / therapeutic use
  • Protein Processing, Post-Translational / drug effects
  • Pyrazines / pharmacology*
  • Pyrazines / therapeutic use
  • Receptor-Interacting Protein Serine-Threonine Kinase 2 / metabolism
  • Tumor Cells, Cultured / drug effects
  • Tumor Cells, Cultured / metabolism
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents
  • Boronic Acids
  • I-kappa B Proteins
  • NF-kappa B
  • NFKBIA protein, human
  • Neoplasm Proteins
  • Nfkbia protein, mouse
  • Protease Inhibitors
  • Pyrazines
  • NF-KappaB Inhibitor alpha
  • Bortezomib
  • RIPK2 protein, human
  • Receptor-Interacting Protein Serine-Threonine Kinase 2
  • I-kappa B Kinase