dc.contributorBaylor Coll Med
dc.contributorUniversidade Federal de São Paulo (UNIFESP)
dc.contributorSichuan Univ
dc.contributorCapital Med Univ
dc.creatorSantos Silva, Kleiton Augusto [UNIFESP]
dc.creatorDong, Jiangling
dc.creatorDong, Yanjun
dc.creatorDong, Yanlan
dc.creatorSchor, Nestor [UNIFESP]
dc.creatorTweardy, David J.
dc.creatorZhang, Liping
dc.creatorMitch, William E.
dc.date.accessioned2016-01-24T14:40:24Z
dc.date.accessioned2023-09-04T18:17:59Z
dc.date.available2016-01-24T14:40:24Z
dc.date.available2023-09-04T18:17:59Z
dc.date.created2016-01-24T14:40:24Z
dc.date.issued2015-04-24
dc.identifierJournal of Biological Chemistry. Bethesda: Amer Soc Biochemistry Molecular Biology Inc, v. 290, n. 17, p. 11177-11187, 2015.
dc.identifier0021-9258
dc.identifierhttp://repositorio.unifesp.br/handle/11600/39011
dc.identifier10.1074/jbc.M115.641514
dc.identifierWOS:000353404500050
dc.identifier.urihttps://repositorioslatinoamericanos.uchile.cl/handle/2250/8612836
dc.description.abstractCachexia 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.languageeng
dc.publisherAmer Soc Biochemistry Molecular Biology Inc
dc.relationJournal of Biological Chemistry
dc.rightsAcesso restrito
dc.titleInhibition of Stat3 Activation Suppresses Caspase-3 and the Ubiquitin-Proteasome System, Leading to Preservation of Muscle Mass in Cancer Cachexia
dc.typeArtigo


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