A new model of cancer cachexia: contribution of the ubiquitin-proteasome pathway.
A new model of cachexia is described in which muscle protein metabolism related to the ubiquitin-proteasome pathway was investigated. Cloning of the colon-26 tumor produced a cell line, termed R-1, which induced cytokine (noninterleukin-1beta, interleukin-6 and tumor necrosis factor-alpha)-independent cachexia. Implantation of R-1 cells in mice elicited significant (20-30%) weight loss and decreased blood glucose by 70%, and adipose tissue levels declined by 95% and muscle weights decreased by 20-25%. Food intake was unaffected. The decrease in muscle weight reflected a decline in insoluble, but not soluble, muscle protein that was associated with a significant increase in net protein degradation. The rate of ubiquitin conjugation of proteins was significantly elevated in muscles of cachectic mice. Furthermore, the proteasome inhibitor lactacystin blocked the increase in protein breakdown but had no significant effect on proteolysis. Several markers of the ubiquitin-proteasome pathway, E2(14k) mRNA and E2(14k) protein and ubiquitin-protein conjugates, were not elevated. Future investigations with this new model should gain further insights into the mechanisms of cachexia and provide a background to evaluate novel and more efficacious therapies.
Lazarus
D D
DD
ProScript, Cambridge 02139, Massachusetts, USA.
Destree
A T
AT
Mazzola
L M
LM
McCormack
T A
TA
Dick
L R
LR
Xu
B
B
Huang
J Q
JQ
Pierce
J W
JW
Read
M A
MA
Coggins
M B
MB
Solomon
V
V
Goldberg
A L
AL
Brand
S J
SJ
Elliott
P J
PJ
D000818:Animals; D002100:Cachexia / Q000188:drug therapy / Q000209:etiology* / Q000378:metabolism*; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D003907:Dexamethasone / Q000627:therapeutic use; D004195:Disease Models, Animal; D005938:Glucocorticoids / Q000627:therapeutic use; D007213:Indomethacin / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D009097:Multienzyme Complexes / Q000378:metabolism*; D009124:Muscle Proteins / Q000378:metabolism; D009132:Muscles / Q000378:metabolism; D009374:Neoplasms, Experimental / Q000150:complications*; D046988:Proteasome Endopeptidase Complex; D014452:Ubiquitins / Q000378:metabolism*
D005938:Glucocorticoids; D009097:Multienzyme Complexes; D009124:Muscle Proteins; D014452:Ubiquitins; D003907:Dexamethasone; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; D007213:Indomethacin