Tautomycetin suppresses the TNFalpha/NF-kappaB pathway via inhibition of IKK activation

Int J Oncol. 2008 Nov;33(5):1027-35.

Abstract

TNFalpha activated NF-kappaB and associated regulatory factors including IKK are strongly implicated in a variety of hematological and solid tumor malignancies. We show that tautomycetin (TC) specifically inhibits activation of NF-kappaB among the three TNFalpha effectors (NF-kappaB, JNK and caspase). TC inhibited T-loop phosphorylation of IKKalpha and IKKbeta, thereby preventing degradation of the NF-kappaB inhibitor, IkappaBalpha. Co-immunoprecipitation experiments revealed that the catalytic subunit of PP1 (PP1C) was involved in the IKK complex. Pull-down analysis using recombinant GST-TNFalpha, showed that PP1C was recruited to TNFR1 together with IKK complex, RIP and TAK1 upon stimulus. These results suggest that the PP1 positively regulates the TNFalpha-induced NF-kappaB pathway at the level of IKK activation. Thus, TC might be used therapeutically to suppress the TNFalpha/NF-kappaB pathway.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • COS Cells
  • Chlorocebus aethiops
  • Dose-Response Relationship, Drug
  • Furans / pharmacology*
  • HeLa Cells
  • Humans
  • I-kappa B Kinase / antagonists & inhibitors*
  • I-kappa B Kinase / genetics
  • I-kappa B Kinase / metabolism
  • I-kappa B Proteins / metabolism
  • Lipids / pharmacology*
  • MAP Kinase Kinase Kinases / metabolism
  • NF-KappaB Inhibitor alpha
  • NF-kappa B / metabolism*
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Phosphatase 1 / metabolism
  • Receptor-Interacting Protein Serine-Threonine Kinases / metabolism
  • Receptors, Tumor Necrosis Factor, Type I / metabolism
  • Recombinant Fusion Proteins / antagonists & inhibitors
  • Recombinant Fusion Proteins / metabolism
  • Recombinant Proteins / metabolism
  • Signal Transduction / drug effects*
  • Time Factors
  • Transfection
  • Tumor Necrosis Factor-alpha / metabolism*

Substances

  • Furans
  • I-kappa B Proteins
  • Lipids
  • NF-kappa B
  • NFKBIA protein, human
  • Protein Kinase Inhibitors
  • Receptors, Tumor Necrosis Factor, Type I
  • Recombinant Fusion Proteins
  • Recombinant Proteins
  • Tumor Necrosis Factor-alpha
  • tautomycetin
  • NF-KappaB Inhibitor alpha
  • Receptor-Interacting Protein Serine-Threonine Kinases
  • I-kappa B Kinase
  • MAP Kinase Kinase Kinases
  • MAP kinase kinase kinase 7
  • Protein Phosphatase 1