Inhibition of Stat3 Activation Suppresses Caspase-3 and the Ubiquitin-Proteasome System, Leading to Preservation of Muscle Mass in Cancer Cachexia

Autor(es)

Santos Silva, Kleiton Augusto ^{[1, 2]} ; Dong, Jiangling ^{[2, 3]} ; Dong, Yanjun ^{[2, 4]} ; Dong, Yanlan ^[2] ; Schor, Nestor ^[1] ; Tweardy, David J. ^{[5, 6, 7]} ; Zhang, Liping ^[2] ; Mitch, William E. ^[2]

Afiliação do(s) autor(es)

^[1] Univ Fed Sao Paulo, Dept Med, Div Nephrol, BR-04023900 Sao Paulo - Brazil

^[2] Baylor Coll Med, Div Nephrol, Dept Med, Houston, TX 77030 - USA

^[3] Sichuan Univ, Coll Life Sci, Chengdu 610065 - Peoples R China

^[4] Capital Med Univ, An Zhen Hosp, Beijing Inst Heart Lung & Blood Vessel Dis, Beijing 100029 - Peoples R China

^[5] Baylor Coll Med, Dept Mol & Cellular Biol, Houston, TX 77030 - USA

^[6] Baylor Coll Med, Dept Med, Sect Infect Dis, Houston, TX 77030 - USA

^[7] Baylor Coll Med, Dept Biochem & Mol Biol, Houston, TX 77030 - USA

• Tipo de documento: Artigo Científico
• Fonte: Journal of Biological Chemistry; v. 290, n. 17, p. 11177-11187, APR 24 2015.
• Citações Web of Science: 53

Resumo

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. (AU)

• Processo FAPESP: 12/03142-8 - Mecanismos e mediadores que estão associados com condições catabólicas no prejuízo funcional da célula satélite: papel dos glicocorticóides
• Beneficiário: Kleiton Augusto dos Santos Silva
• Modalidade de apoio: Bolsas no Exterior - Estágio de Pesquisa - Doutorado