Inhibition of HSP90 reverses STAT3-mediated muscle wasting in cancer
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. 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 tumor-bearing cachectic mice or the myotube
atrophy of C2C12 cells induced by C26 conditional medium. A mechanistic
study indicated that in cachectic skeletal muscle, prolonged STAT3
activation transactivated FOXO1 by binding directly to its promoter and
triggered the muscle wasting in a FOXO1-dependent manner; Our results
demonstrate that the HSP90/STAT3/FOXO1 axis plays a critical role in the
cachectic muscle wasting, which might serve as potential therapeutic
target for the treatment of cancer cachexia.