ELSEVIER Cancer Letters 99 (1996) 7-14 CANCER LETTERS Muscle hypercatabolism during cancer cachexia is not reversed by the glucocorticoid receptor antagonist RU38486 Marta Lloveraa, Cdia Garcia-Martineza, Paola Costellic, New Agellb, Neus Carb&, Francisco J. L6pez-Sorianoa, Josep M. Argil&c* “Dqx~rtument de Rioquimircl i Fisiolngin, Farultat de Biologia, Universitut de Barcelnnu, Diagonul645. 0X07/-Brrrcelona. Spain bDepartament de Biologia Celluhr, Facultat de Medicinn, Universitat de Bnrcelonu. Barcelona, Spain ‘Dipurtimento di Medicina ed Oncologia Sperimentale, Sezione di I’atologiu Generule, Universitd di Torino, Italy Received 29 August 1995;revision received 4 October 1995;accepted I I October 1995 Abstract 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., Garcia-Martinez, C., Agell, N., MarzBbal, M., L6pez-Soriano, F.J. and ArgilBs, J.M. (1994) FEBS Lett., 338, 3 1l-3 181. 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, EM. (1993) Br. J. Cancer, 67, 15-231. In the present study, the role of glucocorticoids in muscle hypercatabolism was investigated using the glucocorticoid receptor an- tagonist 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. Keywords: Cancer cachexia; Skeletal muscle; Glucocorticoids; Protein turnover; Ubiquitin 1. Introduction Cachexia may be a chronic or terminal occurrence in neoplastic disease or it can develop as a relatively acute and early process. It is a complex syndrome * Corresponding author. Tel.: +34 3 4021519; fax: +34 3 4021559. characterized by body weight loss and tissue wasting. In the last few years an appreciable number of ex- perimental [2,41-43] and clinical reports [8,19,20, 321 have underlined that the pivotal metabolic change is the dissipation of nitrogen from host tissues, par- ticularly from the skeletal muscle, that primarily re- flects enhanced protein turnover. The regulators and mechanisms of this altered protein metabolism are not fully clarified, but previous studies suggest that 0304-3835/96/$12.00 0 1996Elsevier Science Ireland Ltd. All rights reserved SSDI 0304-3835(95)04026-Z