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.