Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 290, Issue 17, Pages 11177-11187Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M115.641514
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Funding
- Satellite Health
- American Diabetic Association [1-11-BS-194]
- Diabetes Research Center at Baylor College of Medicine [P30-DK079638]
- National Institutes of Health [R37 DK37175, P50 CA058183, P50 CA097007, R21 CA149783]
- Cancer Prevention and Research Institute of Texas [RP100421]
- Alkek Foundation
- Dan L. Duncan Cancer Center
- Sao Paulo Research Foundation [FAPESP 2012/03142-8]
- Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP) [12/03142-8] Funding Source: FAPESP
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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.
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