Molecular mechanisms of constitutive NF-kappaB/Rel activation in Hodgkin/Reed-Sternberg cells

Oncogene. 1999 Jan 28;18(4):943-53. doi: 10.1038/sj.onc.1202351.

Abstract

A common characteristic of malignant cells derived from patients with Hodgkin's disease (HD) is a high level of constitutive nuclear NF-kappaB/Rel activity, which stimulates proliferation and confers resistance to apoptosis. We have analysed the mechanisms that account for NF-kappaB activation in a panel of Hodgkin/Reed-Sternberg (H-RS) cell lines. Whereas two cell lines (L428 and KMH-2) expressed inactive IkappaBalpha, no significant changes in NF-kappaB or IkappaB expression were seen in other H-RS cells (L591, L1236 and HDLM-2). Constitutive NF-kappaB was susceptible to inhibition by recombinant IkappaBalpha, suggesting that neither mutations in the NF-kappaB genes nor posttranslational modifications of NF-kappaB were involved. Endogenous IkappaBalpha was bound to p65 and displayed a very short half-life. IkappaBalpha degradation could be blocked by inhibitors of the NF-kappaB activating pathway. Proteasomal inhibition caused an accumulation of phosphorylated IkappaBalpha and a reduction of NF-kappaB activity in HDLM-2 and L1236 cells. By in vitro kinase assays we demonstrate constitutive IkappaB kinase (IKK) activity in H-RS cells, indicating ongoing signal transduction. Furthermore, H-RS cells secrete one or more factor(s) that were able to trigger NF-kappaB activation. We conclude that aberrant activation of IKK's, and in some cases defective IkappaBs, lead to constitutive nuclear NF-kappaB activity, which in turn results in a growth advantage of Hodgkin's disease tumor cells.

MeSH terms

  • Animals
  • DNA-Binding Proteins / metabolism*
  • Enzyme Activation
  • HeLa Cells
  • Humans
  • I-kappa B Kinase
  • I-kappa B Proteins*
  • L Cells
  • Mice
  • NF-KappaB Inhibitor alpha
  • NF-kappa B / antagonists & inhibitors
  • NF-kappa B / genetics
  • NF-kappa B / metabolism*
  • Neoplasm Proteins / metabolism*
  • Protein-Serine-Threonine Kinases / metabolism*
  • Reed-Sternberg Cells / metabolism*
  • Transcription Factor RelA
  • Tumor Cells, Cultured

Substances

  • DNA-Binding Proteins
  • I-kappa B Proteins
  • NF-kappa B
  • NFKBIA protein, human
  • Neoplasm Proteins
  • Nfkbia protein, mouse
  • Transcription Factor RelA
  • NF-KappaB Inhibitor alpha
  • Protein-Serine-Threonine Kinases
  • CHUK protein, human
  • Chuk protein, mouse
  • I-kappa B Kinase
  • IKBKB protein, human
  • IKBKE protein, human
  • Ikbkb protein, mouse
  • Ikbke protein, mouse