title: IGF-1 is downregulated in experimental cancer cachexia.
abstract: 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 approximately 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-alpha synthesis, alone or combined with formoterol, a beta(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.
authors.affiliation: Dipartimento di Medicina e Oncologia Sperimentale, Università di Torino, Turin, Italy. paola.costelli@unito.it
authors.forename: Paola
authors.initials: P
authors.lastname: Costelli
authors.forename: Maurizio
authors.initials: M
authors.lastname: Muscaritoli
authors.forename: Maurizio
authors.initials: M
authors.lastname: Bossola
authors.forename: Fabio
authors.initials: F
authors.lastname: Penna
authors.forename: Patrizia
authors.initials: P
authors.lastname: Reffo
authors.forename: Andrea
authors.initials: A
authors.lastname: Bonetto
authors.forename: Silvia
authors.initials: S
authors.lastname: Busquets
authors.forename: Gabriella
authors.initials: G
authors.lastname: Bonelli
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Lopez-Soriano
authors.forename: Giovanni Battista
authors.initials: GB
authors.lastname: Doglietto
authors.forename: Josep M
authors.initials: JM
authors.lastname: Argilés
authors.forename: Francesco M
authors.initials: FM
authors.lastname: Baccino
authors.forename: Filippo
authors.initials: F
authors.lastname: Rossi Fanelli
mesh_terms: D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D002100:Cachexia / Q000378:metabolism*; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004983:Ethanolamines / Q000494:pharmacology; D000068759:Formoterol Fumarate; D005786:Gene Expression Regulation; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D008297:Male; D009124:Muscle Proteins / Q000378:metabolism; D018482:Muscle, Skeletal; D009374:Neoplasms, Experimental / Q000378:metabolism*; D010431:Pentoxifylline / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D044843:SKP Cullin F-Box Protein Ligases / Q000378:metabolism; D000070584:Tripartite Motif Proteins; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
chemical_list: D000318:Adrenergic beta-Agonists; D004791:Enzyme Inhibitors; D004983:Ethanolamines; D009124:Muscle Proteins; D000070584:Tripartite Motif Proteins; D025801:Ubiquitin; D007334:Insulin-Like Growth Factor I; C486692:Fbxo32 protein, rat; D044843:SKP Cullin F-Box Protein Ligases; C499086:Trim63 protein, rat; D044767:Ubiquitin-Protein Ligases; D017526:Receptor, IGF Type 1; D010431:Pentoxifylline; D000068759:Formoterol Fumarate