Introduction
Cancer cachexia is a devastating metabolic syndrome that affects up to
80% of cancer patients and accounts for nearly 20% of all
cancer-related deaths. Skeletal muscle wasting is one of the most
crucial pathological events in cancer cachexia. As a highly plastic
tissue, skeletal muscle can change its mass, function, and metabolism in
response to various endogenous or exogenous stimuli. Current evidence
indicates that the imbalance between catabolic and anabolic responses,
the disorder of protein synthesis and degradation pathways, including
both the ubiquitin-proteasome system (UPS) and the autophagy-lysosome
pathway (ALP), are the major causes of cachectic muscle wasting
(Bilodeau, Coyne & Wing, 2016). In cancer cachexia, UPS activation is
thought to mediate muscle atrophy, and the enhanced expression of
muscle-specific E3 ubiquitin ligases, such as muscle-atrophy-F-box
(MAFbx/Atrogin-1) and muscle-RING-finger-1 (MuRF1), are hallmarks of
this process (Bodine et al., 2001; Guadagnin, Mazala & Chen, 2018; Guo,
Wang, Wang, Qiao & Tang, 2017). However, the upstream activators of the
protein degradation pathway and the molecular mechanisms involved in
muscle wasting in cancer cachexia are still largely unknown.
Signal transducer and activator of transcription 3
(STAT3) plays a critical role in
cancer cachexia, and increased STAT3 activation (in muscle) has been
found in multiple types of experimental cancer cachexia. (Ma, Sanchez,
Hall, Tremblay, Di Marco & Gallouzi, 2017; Mubaid et al., 2019; Silva
et al., 2015) In experimental cancer cachexia, muscle-specific STAT3
depletion or JAK2/STAT3 pathway inhibition can reverse the skeletal
muscle wasting phenotype(Bonetto et al., 2012). However, its clinical
association, the reason for prolonged STAT3 activation in cachectic
muscles, and its contribution to pathological anabolic responses in
muscle still need to be defined.
HSP90 (heat shock protein 90) is an evolutionarily conserved molecular
chaperone that is essential for cell growth, proliferation,
transformation, proliferation, and survival under normal and stress
conditions (Schopf, Biebl & Buchner, 2017). HSP90 interacts extensively
with a variety of signaling transduction proteins (Whitesell &
Lindquist, 2005),(Mahendrarajah et al., 2017). We and other groups have
previously demonstrated that HSP90 could directly interact and regulate
STAT3 activation in various cancers and promote cancer cell growth and
survival as an oncogene (Prinsloo, Kramer, Edkins & Blatch, 2012;
Schoof, von Bonin, Trumper & Kube, 2009; Song et al., 2017). However,
whether HSP90 is involved in regulating STAT3 activation in skeletal
muscles and its functional role in cachectic muscle wasting is still
unknown.
Herein, we report that the increased HSP90-STAT3 interaction is
necessary to induce prolonged STAT3 activation and muscle atrophy in
clinical cachectic patients and C26 tumor-bearing experimental cachexia
mice models. Administration of HSP90 inhibitors in vivo could
successfully alleviate the pathological development of experimental
cachexia; mechanistic study demonstrated that activated STAT3 could
induce FOXO1 transcription by binding directly to the FOXO1 promoter,
and knockdown of FOXO1 abolished the effects of STAT3 induced muscle
wasting. Therefore, our study provided novel experimental evidence
showing that the HSP90/STAT3/FOXO1 axis might be a potential therapeutic
target for cancer cachexia.