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INFLAMMATION AND CYTOKINES

IGF-1 is downregulated in experimental cancer cachexia

¹Dipartimento di Medicina e Oncologia Sperimentale, Università di Torino, Turin; ²Dipartimento di Medicina Clinica, Università La Sapienza, Rome; ³Istituto di Clinica Chirurgica, Università Cattolica, Rome, Italy; and ⁴Departament de Bioquìmica i Biologia Molecular, Universitat de Barcelona, Barcelona, Spain

Submitted 10 February 2006 ; accepted in final form 31 March 2006

Cancer cachexia is characterized by skeletal muscle wasting that is mainly supported by hypercatabolism. Muscle atrophy has been suggested to depend on impaired IGF-1 signal transduction pathway. The present study has been aimed at investigating the IGF-1 system in rats bearing the AH-130 hepatoma, a well-characterized model of cachexia. IGF-1 mRNA expression in the gastrocnemius of tumor hosts progressively decreases to 50% of controls. By contrast, both IGF-1 receptor and insulin receptor mRNA levels increase in day 7 AH-130 hosts. IGF-1 and insulin circulating levels, as well as IGF-1 expression in the liver, are reduced. Muscle wasting in the AH-130 bearers is associated with hyperactivation of the ubiquitin-proteasome system. Consistently, the mRNA levels of ubiquitin and of the ubiquitin ligases atrogin-1 and MuRF1 are significantly increased in the gastrocnemius of day 7 AH-130 hosts. Exogenous IGF-1 administered to tumor bearers does not prevent cachexia. IGF-1 mRNA levels also have been evaluated in the gastrocnemius of AH-130 hosts treated with pentoxifylline, an inhibitor of TNF- synthesis, alone or combined with formoterol, a ₂-adrenergic agonist. Both treatments partially correct muscle atrophy without modifying IGF-1 and atrogin-1 mRNA levels, whereas MuRF1 hyperexpression is reduced by the combination of pentoxifylline with formoterol. These results demonstrate for the first time that the IGF-1 system is downregulated in cancer cachexia, although the underlying mechanism remains unknown. Moreover, no simple relation linking IGF-1 and/or atrogin-1 mRNA levels and muscle atrophy could be observed in these experimental conditions. Further studies are thus needed to clarify both issues.

insulin-like growth factor-1; muscle wasting; atrogin-1; pentoxifylline; formoterol

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