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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

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

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Author(s):
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]
Total Authors: 8
Affiliation:
[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
Total Affiliations: 7
Document type: Journal article
Source: Journal of Biological Chemistry; v. 290, n. 17, p. 11177-11187, APR 24 2015.
Web of Science Citations: 53
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. (AU)

FAPESP's process: 12/03142-8 - Mechanisms and mediators that are associated with catabolic conditions to impair satellite cell function: role of glucocorticoids
Grantee:Kleiton Augusto dos Santos Silva
Support Opportunities: Scholarships abroad - Research Internship - Doctorate