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J Biol Chem. 2015 Apr 24;290(17):11177-87. doi: 10.1074/jbc.M115.641514. Epub 2015 Mar 18.

Inhibition of Stat3 activation suppresses caspase-3 and the ubiquitin-proteasome system, leading to preservation of muscle mass in cancer cachexia.

Author information

1
From the Nephrology Division, Department of Medicine, and the Nephrology Division, Department of Medicine, Federal University of Sao Paulo, Sao Paulo 04023-900, Brazil.
2
From the Nephrology Division, Department of Medicine, and the College of Life Sciences, Sichuan University, Chengdu 610065, China, and.
3
From the Nephrology Division, Department of Medicine, and the Beijing Institute of Heart, Lung, and Blood Vessel Diseases, An Zhen Hospital Affiliated to Capital Medical University, Beijing 100029, China.
4
From the Nephrology Division, Department of Medicine, and.
5
the Nephrology Division, Department of Medicine, Federal University of Sao Paulo, Sao Paulo 04023-900, Brazil.
6
the Departments of Medicine (Section of Infectious Diseases), Molecular and Cellular Biology, and Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas 77030.
7
From the Nephrology Division, Department of Medicine, and lipingz@bcm.edu.

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 δ (C/EBPδ). 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/EBPδ to myostatin and expression of MAFbx/Atrogin-1 and increases the ubiquitin-proteasome system. Indeed, C/EBPδ 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.

KEYWORDS:

Cancer Biology; Cancer Cachexia; Caspase; Caspase-3; Muscle Atrophy; STAT3; Ubiquitin

PMID:
25787076
PMCID:
PMC4409274
DOI:
10.1074/jbc.M115.641514
[Indexed for MEDLINE]
Free PMC Article

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