Inhibition of HSP90 reverses STAT3-mediated muscle wasting in cancer cachexia mice.

Background and purpose Cancer cachexia is one of the most common causes of death among cancer patients; no effective anti-cachectic treatment is currently available. In experimental cachectic animal models, aberrant activation of STAT3 in skeletal muscle has been found to contribute to muscle wasting. However, its clinical association, the factors regulating STAT3 activation, and the molecular mechanisms remain incompletely understood. Experimental approach The expression of HSP90 and the activation of STAT3 were detected in muscle from the patients with cancer cachexia or the tumour-bearing cachectic mice. HSP90 inhibitors, including 17DMAG and PU-H71, were administered to cachexic mice, and cachexia parameters, such as weight loss, food intake, survival rate, body composition, serum metabolites, muscle wasting pathology, and catabolic activation, were measured and analyzed. The in vitro coculture of C2C12 myotube cells with C26 conditioned media (CM) was performed to address the pathological mechanism of catabolic muscle wasting. The roles of HSP90, STAT3, and FOXO1 in myotube atrophy were explored via overexpression or knockdown. Results Here, we show that an enhanced interaction between activated STAT3 and HSP90, which were observed in the skeletal muscle of cancer cachexia patients, is a crucial event for the development of cachectic muscle wasting. Administration of HSP90 inhibitors 17DMAG and PU-H71 alleviated the muscle wasting in C26 and LLC tumor-bearing cachectic mice models or the myotube atrophy of C2C12 cells induced by C26 conditional medium. Prolonged STAT3 activation transactivated FOXO1 by binding directly to its promoter and triggered the muscle wasting in a FOXO1-dependent manner in muscle cells. Conclusion and implications Our results demonstrate that the HSP90/STAT3/FOXO1 axis plays a critical role in cachectic muscle wasting, which might serve as a potential therapeutic target for the treatment of cancer cachexia.