Muscle hypercatabolism during cancer cachexia is not reversed by the glucocorticoid receptor antagonist RU38486.
In rats into which a fast growing ascites hepatoma (Yoshida AH-130) had been transplanted, tumor growth elicited a marked loss of body weight and tissue waste, particularly of the skeletal muscle. This depletion has been associated with enhanced rates of protein breakdown, mainly due to hyperactivation of the ATP-ubiquitin-dependent proteolytic system [Llovera, M., García-Martínez, C., Agell, N., Marzábal, M., López-Soriano, F.J. and Argilés, J.M. (1994) FEBS Lett., 338, 311-318]. Profound alterations of the hormonal status and the production of tumor necrosis factor have been involved in the development of such wasting syndrome [Tessitore, L., Costelli, P. and Baccino, F.M. (1993) Br. J. Cancer, 67, 15-23]. In the present study, the role of glucocorticoids in muscle hypercatabolism was investigated using the glucocorticoid receptor antagonist RU38486. The treatment with this drug was unable to interfere with the development of cachexia in the AH-130 hosts with regard to tissue weight as well as to muscle protein turnover rates. As one would expect, the RU38486 was also ineffective in lowering both the expression of ubiquitin mRNA and the degree of muscle protein ubiquitinization in AH-130 bearers. These data allow us to exclude that glucocorticoids play a direct crucial role in the development of cachexia in this tumor model.
Llovera
M
M
Departament de Bioquímica i Fisiologia, Facultat de Biologia, Universitat de Barcelona, Spain.
García-Martínez
C
C
Costelli
P
P
Agell
N
N
Carbó
N
N
López-Soriano
F J
FJ
Argilés
J M
JM
D000818:Animals; D002100:Cachexia / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism*; D003345:Corticosterone / Q000097:blood; D005938:Glucocorticoids / Q000378:metabolism; D006727:Hormone Antagonists / Q000494:pharmacology*; D008114:Liver Neoplasms, Experimental / Q000150:complications / Q000378:metabolism*; D008297:Male; D015735:Mifepristone / Q000494:pharmacology*; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors*; D014452:Ubiquitins / Q000378:metabolism
D005938:Glucocorticoids; D006727:Hormone Antagonists; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D011965:Receptors, Glucocorticoid; D014452:Ubiquitins; D015735:Mifepristone; D003345:Corticosterone