Inhibition of Stat3 suppresses caspase-3 and the ubiquitin-proteasome system leading to preservation of muscle mass in cancer cachexia [Molecular Bases of Disease]

March 18th, 2015 by Silva, K. A. S., Dong, J., Dong, Y., , Schor, N., Tweardy, D. J., Zhang, L., Mitch, W. E.

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 media from C26 colon carcinoma (C26) or Lewis lung carcinoma (LLC) cells activate 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 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 LLC or C26 tumors, knockout 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 increased ubiquitin-proteasome system (UPS). 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 UPS. These results could lead to novel strategies for preventing cancer-induced muscle wasting.
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