Induction of proteasome expression in skeletal muscle is attenuated by inhibitors of NF-kappaB activation.
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.
Wyke
S M
SM
Pharmaceutical Sciences Research Institute, Aston University, Birmingham B4 7ET, UK.
Russell
S T
ST
Tisdale
M J
MJ
D000818:Animals; D001798:Blood Proteins / Q000378:metabolism; D002100:Cachexia / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D002918:Chymotrypsin / Q000378:metabolism; D003474:Curcumin / Q000494:pharmacology; D024202:Electrophoretic Mobility Shift Assay; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D020672:I-kappa B Proteins / Q000378:metabolism; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000378:metabolism; D018482:Muscle, Skeletal / Q000201:enzymology*; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009374:Neoplasms, Experimental / Q000378:metabolism* / Q000473:pathology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D011509:Proteoglycans; D000077185:Resveratrol; D013267:Stilbenes / Q000494:pharmacology; D014452:Ubiquitins / Q000378:metabolism; D015431:Weight Loss / Q000187:drug effects
D001798:Blood Proteins; D004791:Enzyme Inhibitors; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606205:Nfkbia protein, mouse; D011509:Proteoglycans; D013267:Stilbenes; D014452:Ubiquitins; C042057:proteolysis-inducing peptide; D000072000:NF-KappaB Inhibitor alpha; D002918:Chymotrypsin; D046988:Proteasome Endopeptidase Complex; D003474:Curcumin; D000077185:Resveratrol