Induction of proteasome expression in skeletal muscle is attenuated by inhibitors of NF-kappaB activation

Br J Cancer. 2004 Nov 1;91(9):1742-50. doi: 10.1038/sj.bjc.6602165.


The potential for inhibitors of nuclear factor-kappaB (NF-kappaB) activation to act as inhibitors of muscle protein degradation in cancer cachexia has been evaluated both in vitro and in vivo. Activation of NF-kappaB is important in the induction of proteasome expression and protein degradation by the tumour factor, proteolysis-inducing factor (PIF), since the cell permeable NF-kappaB inhibitor SN50 (18 microM) attenuated the expression of 20S proteasome alpha-subunits, two subunits of the 19S regulator MSS1 and p42, and the ubiquitin-conjugating enzyme, E2(14k), as well as the decrease in myosin expression in murine myotubes. To assess the potential therapeutic benefit of NF-kappaB inhibitors on muscle atrophy in cancer cachexia, two potential inhibitors were employed; curcumin (50 microM) and resveratrol (30 microM). Both agents completely attenuated total protein degradation in murine myotubes at all concentrations of PIF, and attenuated the PIF-induced increase in expression of the ubiquitin-proteasome proteolytic pathway, as determined by the 'chymotrypsin-like' enzyme activity, proteasome subunits and E2(14k). However, curcumin (150 and 300 mg kg(-1)) was ineffective in preventing weight loss and muscle protein degradation in mice bearing the MAC16 tumour, whereas resveratrol (1 mg kg(-1)) significantly attenuated weight loss and protein degradation in skeletal muscle, and produced a significant reduction in NF-kappaB DNA-binding activity. The inactivity of curcumin was probably due to a low bioavailability. These results suggest that agents which inhibit nuclear translocation of NF-kappaB may prove useful for the treatment of muscle wasting in cancer cachexia.

MeSH terms

  • Animals
  • Blood Proteins / metabolism
  • Cachexia / metabolism*
  • Cachexia / pathology
  • Cells, Cultured
  • Chymotrypsin / metabolism
  • Curcumin / pharmacology
  • Electrophoretic Mobility Shift Assay
  • Enzyme Activation
  • Enzyme Inhibitors / pharmacology*
  • I-kappa B Proteins / metabolism
  • Male
  • Mice
  • Mice, Inbred Strains
  • Muscle Fibers, Skeletal / drug effects
  • Muscle Fibers, Skeletal / metabolism
  • Muscle, Skeletal / enzymology*
  • NF-KappaB Inhibitor alpha
  • NF-kappa B / antagonists & inhibitors
  • NF-kappa B / metabolism*
  • Neoplasms, Experimental / metabolism*
  • Neoplasms, Experimental / pathology
  • Proteasome Endopeptidase Complex / metabolism*
  • Proteoglycans
  • Resveratrol
  • Stilbenes / pharmacology
  • Ubiquitins / metabolism
  • Weight Loss / drug effects


  • Blood Proteins
  • Enzyme Inhibitors
  • I-kappa B Proteins
  • NF-kappa B
  • Nfkbia protein, mouse
  • Proteoglycans
  • Stilbenes
  • Ubiquitins
  • proteolysis-inducing peptide
  • NF-KappaB Inhibitor alpha
  • Chymotrypsin
  • Proteasome Endopeptidase Complex
  • Curcumin
  • Resveratrol