dc.contributor | Baylor Coll Med | |
dc.contributor | Universidade Federal de São Paulo (UNIFESP) | |
dc.contributor | Sichuan Univ | |
dc.contributor | Capital Med Univ | |
dc.creator | Santos Silva, Kleiton Augusto [UNIFESP] | |
dc.creator | Dong, Jiangling | |
dc.creator | Dong, Yanjun | |
dc.creator | Dong, Yanlan | |
dc.creator | Schor, Nestor [UNIFESP] | |
dc.creator | Tweardy, David J. | |
dc.creator | Zhang, Liping | |
dc.creator | Mitch, William E. | |
dc.date.accessioned | 2016-01-24T14:40:24Z | |
dc.date.accessioned | 2023-09-04T18:17:59Z | |
dc.date.available | 2016-01-24T14:40:24Z | |
dc.date.available | 2023-09-04T18:17:59Z | |
dc.date.created | 2016-01-24T14:40:24Z | |
dc.date.issued | 2015-04-24 | |
dc.identifier | Journal of Biological Chemistry. Bethesda: Amer Soc Biochemistry Molecular Biology Inc, v. 290, n. 17, p. 11177-11187, 2015. | |
dc.identifier | 0021-9258 | |
dc.identifier | http://repositorio.unifesp.br/handle/11600/39011 | |
dc.identifier | 10.1074/jbc.M115.641514 | |
dc.identifier | WOS:000353404500050 | |
dc.identifier.uri | https://repositorioslatinoamericanos.uchile.cl/handle/2250/8612836 | |
dc.description.abstract | Cachexia occurs in patients with advanced cancers. Despite the adverse clinical impact of cancer-induced muscle wasting, pathways causing cachexia are controversial, and clinically reliable therapies are not available. A trigger of muscle protein loss is the Jak/Stat pathway, and indeed, we found that conditioned medium from C26 colon carcinoma (C26) or Lewis lung carcinoma cells activates Stat3 (p-Stat3) in C2C12 myotubes. We identified two proteolytic pathways that are activated in muscle by p-Stat3; one is activation of caspase-3, and the other is p-Stat3 to myostatin, MAFbx/Atrogin-1, and MuRF-1 via CAAT/enhancer-binding protein delta (C/EBP delta). Using sequential deletions of the caspase-3 promoter and CHIP assays, we determined that Stat3 activation increases caspase-3 expression in C2C12 cells. Caspase-3 expression and proteolytic activity were stimulated by p-Stat3 in muscles of tumor-bearing mice. in mice with cachexia caused by Lewis lung carcinoma or C26 tumors, knock-out of p-Stat3 in muscle or with a small chemical inhibitor of p-Stat3 suppressed muscle mass losses, improved protein synthesis and degradation in muscle, and increased body weight and grip strength. Activation of p-Stat3 stimulates a pathway from C/EBP delta to myostatin and expression of MAFbx/Atrogin-1 and increases the ubiquitin-proteasome system. Indeed, C/EBP delta KO decreases the expression of MAFbx/Atrogin-1 and myostatin, while increasing muscle mass and grip strength. in conclusion, cancer stimulates p-Stat3 in muscle, activating protein loss by stimulating caspase-3, myostatin, and the ubiquitin-proteasome system. These results could lead to novel strategies for preventing cancer-induced muscle wasting. | |
dc.language | eng | |
dc.publisher | Amer Soc Biochemistry Molecular Biology Inc | |
dc.relation | Journal of Biological Chemistry | |
dc.rights | Acesso restrito | |
dc.title | Inhibition of Stat3 Activation Suppresses Caspase-3 and the Ubiquitin-Proteasome System, Leading to Preservation of Muscle Mass in Cancer Cachexia | |
dc.type | Artigo | |