Frequent engagement of RelB activation is critical for cell survival in multiple myeloma

PLoS One. 2013;8(3):e59127. doi: 10.1371/journal.pone.0059127. Epub 2013 Mar 28.

Abstract

The NF-κB family of transcription factors has emerged as a key player in the pathogenesis of multiple myeloma (MM). NF-κB is activated by at least two major signaling pathways. The classical pathway results in the activation of mainly RelA containing dimers, whereas the alternative pathway leads to the activation of RelB/p52 and RelB/p50 heterodimers. Activating mutations in regulators of the alternative pathway have been identified in 17% of MM patients. However, the status of RelB activation per se and its role in the regulation of cell survival in MM has not been investigated. Here, we reveal that 40% of newly diagnosed MM patients have a constitutive RelB DNA-binding activity in CD138(+) tumor cells, and we show an association with increased expression of a subset of anti-apoptotic NF-κB target genes, such as cIAP2. Furthermore, we demonstrate that RelB exerts a crucial anti-apoptotic activity in MM cells. Our findings indicate that RelB activation is key for promoting MM cell survival through the upregulation of anti-apoptotic proteins. Altogether, our study provides the framework for the development of new molecules targeting RelB in the treatment of MM.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Apoptosis
  • Baculoviral IAP Repeat-Containing 3 Protein
  • Cell Survival
  • DNA / metabolism
  • Female
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Inhibitor of Apoptosis Proteins / genetics*
  • Inhibitor of Apoptosis Proteins / metabolism
  • Male
  • Middle Aged
  • Multiple Myeloma / genetics*
  • Multiple Myeloma / metabolism
  • Multiple Myeloma / pathology
  • Primary Cell Culture
  • Signal Transduction
  • Syndecan-1 / genetics
  • Syndecan-1 / metabolism
  • Transcription Factor RelA / genetics
  • Transcription Factor RelA / metabolism
  • Transcription Factor RelB / genetics*
  • Transcription Factor RelB / metabolism
  • Transcription, Genetic*
  • Ubiquitin-Protein Ligases

Substances

  • Inhibitor of Apoptosis Proteins
  • RELA protein, human
  • RELB protein, human
  • SDC1 protein, human
  • Syndecan-1
  • Transcription Factor RelA
  • Transcription Factor RelB
  • DNA
  • BIRC3 protein, human
  • Baculoviral IAP Repeat-Containing 3 Protein
  • Ubiquitin-Protein Ligases

Grant support

This work was supported by grants to V.B. from Agence Nationale pour la Recherche (ANR), Association pour la Recherche sur le Cancer, Belgian InterUniversity Attraction Pole, Cancéropole Ile-de-France, research fellowship from Association CANCEN (Tours, France) (H.M.), and doctoral fellowships from Ministère de la Recherche et des Technologies and Société Française d'Hématologie (F.C.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.