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

• Published in: The Journal of biological chemistry Vol. 290; no. 17; pp. 11177 - 11187
• Main Authors: Silva, Kleiton Augusto Santos, Dong, Jiangling, Dong, Yanjun, Dong, Yanlan, Schor, Nestor, Tweardy, David J., Zhang, Liping, Mitch, William E.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 24.04.2015; American Society for Biochemistry and Molecular Biology
• Subjects: Animals; Cachexia - genetics; Cachexia - metabolism; Cachexia - pathology; Cancer Biology; Cancer Cachexia; Carcinoma, Lewis Lung - genetics; Carcinoma, Lewis Lung - metabolism; Carcinoma, Lewis Lung - pathology; Caspase; Caspase 3 - genetics; Caspase 3 - metabolism; Caspase-3; CCAAT-Enhancer-Binding Protein-delta - genetics; CCAAT-Enhancer-Binding Protein-delta - metabolism; Cell Line, Tumor; Colonic Neoplasms - genetics; Colonic Neoplasms - metabolism; Colonic Neoplasms - pathology; Mice; Mice, Knockout; Muscle Atrophy; Muscle Proteins - genetics; Muscle Proteins - metabolism; Muscle, Skeletal - metabolism; Muscle, Skeletal - pathology; Myostatin - genetics; Myostatin - metabolism; Proteasome Endopeptidase Complex - genetics; Proteasome Endopeptidase Complex - metabolism; Proteolysis; Signal Transduction; SKP Cullin F-Box Protein Ligases - genetics; SKP Cullin F-Box Protein Ligases - metabolism; STAT3; STAT3 Transcription Factor - genetics; STAT3 Transcription Factor - metabolism; Tripartite Motif Proteins; Ubiquitin; Ubiquitin - genetics; Ubiquitin - metabolism; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - metabolism; Ubiquitin; STAT3; Caspase; Cancer Cachexia; Cancer Biology; Muscle Atrophy; Caspase-3
• ISSN: 0021-9258; 1083-351X; 1083-351X
• DOI: 10.1074/jbc.M115.641514

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. Background: No reliable treatment exists for cancer-related muscle loss. Results: In muscles of mice with cancer, p-Stat3 stimulates proteolysis by activating caspase-3 and the ubiquitin-proteasome system through a C/EBPδ and myostatin pathway. Conclusion: Inhibition of Stat3 suppresses cancer-induced muscle losses. Significance: A small-molecule Stat3 inhibitor could be integrated into therapeutic strategies for preventing cancer-induced muscle losses.