Running title: Stat3 activates proteolysis in cancer cachexia

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

[1]  J. Iovanna,et al.  Pancreatic Cancer‐Induced Cachexia Is Jak2‐Dependent in Mice , 2014, Journal of cellular physiology.

[2]  J. Carson,et al.  Skeletal muscle glycoprotein 130's role in Lewis lung carcinoma–induced cachexia , 2014, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[3]  A. Goldberg,et al.  Myostatin/activin pathway antagonism: molecular basis and therapeutic potential. , 2013, The international journal of biochemistry & cell biology.

[4]  A. Dingemans,et al.  Nuclear transcription factor κ B activation and protein turnover adaptations in skeletal muscle of patients with progressive stages of lung cancer cachexia. , 2013, The American journal of clinical nutrition.

[5]  W. Mitch,et al.  Signal regulatory protein-α interacts with the insulin receptor contributing to muscle wasting in chronic kidney disease , 2013, Kidney international.

[6]  T. Zimmers,et al.  JAK/STAT3 pathway inhibition blocks skeletal muscle wasting downstream of IL-6 and in experimental cancer cachexia. , 2012, American journal of physiology. Endocrinology and metabolism.

[7]  R. Price,et al.  IL-6 regulation on skeletal muscle mitochondrial remodeling during cancer cachexia in the ApcMin/+ mouse , 2012, Skeletal Muscle.

[8]  Guohua Zhang,et al.  C/EBPβ mediates tumour‐induced ubiquitin ligase atrogin1/MAFbx upregulation and muscle wasting , 2011, The EMBO journal.

[9]  T. Zimmers,et al.  STAT3 Activation in Skeletal Muscle Links Muscle Wasting and the Acute Phase Response in Cancer Cachexia , 2011, PloS one.

[10]  M. J. Ruiz,et al.  Stat3 signaling in acute myeloid leukemia: ligand-dependent and -independent activation and induction of apoptosis by a novel small-molecule Stat3 inhibitor. , 2011, Blood.

[11]  W. Mitch,et al.  Pharmacological inhibition of myostatin suppresses systemic inflammation and muscle atrophy in mice with chronic kidney disease , 2011, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[12]  D. Lacey,et al.  Reversal of Cancer Cachexia and Muscle Wasting by ActRIIB Antagonism Leads to Prolonged Survival , 2010, Cell.

[13]  W. Mitch,et al.  Caspase-3 Cleaves Specific 19 S Proteasome Subunits in Skeletal Muscle Stimulating Proteasome Activity* , 2010, The Journal of Biological Chemistry.

[14]  D. Berrigan,et al.  C/EBPbeta regulates body composition, energy balance-related hormones and tumor growth. , 2009, Carcinogenesis.

[15]  M. Tisdale.  Mechanisms of cancer cachexia. , 2009, Physiological reviews.

[16]  D. Tweardy,et al.  Chemical Probes that Competitively and Selectively Inhibit Stat3 Activation , 2009, PloS one.

[17]  W. Mitch,et al.  IL-6 and serum amyloid A synergy mediates angiotensin II-induced muscle wasting. , 2009, Journal of the American Society of Nephrology : JASN.

[18]  P. Ponikowski,et al.  Cachexia: a new definition. , 2008, Clinical nutrition.

[19]  D. Chinkes,et al.  Pathophysiologic Response to Severe Burn Injury , 2008, Annals of surgery.

[20]  Two tales concerning skeletal muscle. , 2007, The Journal of clinical investigation.

[21]  D. Allen,et al.  Regulation of myostatin expression and myoblast differentiation by FoxO and SMAD transcription factors , 2007 .

[22]  D. Sassoon,et al.  Muscle cachexia is regulated by a p53-PW1/Peg3-dependent pathway. , 2006, Genes & development.

[23]  W. Mitch,et al.  Development of a diagnostic method for detecting increased muscle protein degradation in patients with catabolic conditions. , 2006, Journal of the American Society of Nephrology : JASN.

[24]  W. Mitch,et al.  Insulin resistance accelerates muscle protein degradation: Activation of the ubiquitin-proteasome pathway by defects in muscle cell signaling. , 2006, Endocrinology.

[25]  C. Dejong,et al.  The cachectic mediator proteolysis inducing factor activates NF-kappaB and STAT3 in human Kupffer cells and monocytes. , 2005, International journal of oncology.

[26]  R. Mooney,et al.  Interleukin-6 depletion selectively improves hepatic insulin action in obesity. , 2005, Endocrinology.

[27]  D. Hebenstreit,et al.  JAK/STAT-dependent gene regulation by cytokines. , 2005, Drug news & perspectives.

[28]  W. Mitch,et al.  Regulation of muscle protein degradation: coordinated control of apoptotic and ubiquitin-proteasome systems by phosphatidylinositol 3 kinase. , 2004, Journal of the American Society of Nephrology : JASN.

[29]  Marco Sandri,et al.  Foxo Transcription Factors Induce the Atrophy-Related Ubiquitin Ligase Atrogin-1 and Cause Skeletal Muscle Atrophy , 2004, Cell.

[30]  W. Mitch,et al.  Activation of caspase-3 is an initial step triggering accelerated muscle proteolysis in catabolic conditions. , 2004, The Journal of clinical investigation.

[31]  S. Bhasin,et al.  Glucocorticoid-induced skeletal muscle atrophy is associated with upregulation of myostatin gene expression. , 2003, American journal of physiology. Endocrinology and metabolism.

[32]  M. Tisdale.  Cachexia in cancer patients , 2002, Nature Reviews Cancer.

[33]  S. Bhasin,et al.  Characterization of 5'-regulatory region of human myostatin gene: regulation by dexamethasone in vitro. , 2001, American journal of physiology. Endocrinology and metabolism.

[34]  D J Glass,et al.  Identification of Ubiquitin Ligases Required for Skeletal Muscle Atrophy , 2001, Science.

[35]  S. Gordon,et al.  Skeletal muscle myostatin mRNA expression is fiber-type specific and increases during hindlimb unloading. , 1999, American journal of physiology. Regulatory, integrative and comparative physiology.

[36]  M. Tisdale.  New cachexic factors. , 1998, Current opinion in clinical nutrition and metabolic care.

[37]  A. Goldberg,et al.  Importance of the ATP-Ubiquitin-Proteasome Pathway in the Degradation of Soluble and Myofibrillar Proteins in Rabbit Muscle Extracts* , 1996, The Journal of Biological Chemistry.

[38]  K. Fearon,et al.  Characterization of a cancer cachectic factor , 1996, Nature.

[39]  M. Yano,et al.  Interleukin 6 receptor antibody inhibits muscle atrophy and modulates proteolytic systems in interleukin 6 transgenic mice. , 1996, The Journal of clinical investigation.

[40]  H. Ishitsuka,et al.  Establishment and characterization of cachexia‐inducing and ‐non‐inducing clones of murine colon 26 carcinoma , 1995, International journal of cancer.

[41]  M. Goodman.  Interleukin-6 Induces Skeletal Muscle Protein Breakdown in Rats , 1994, Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine.

[42]  M. Goodman.  Tumor necrosis factor induces skeletal muscle protein breakdown in rats. , 1991, The American journal of physiology.

[43]  W. Mitch,et al.  Comparison of protein synthesis and degradation in incubated and perfused muscle. , 1983, The Biochemical journal.

[44]  P. Fürst,et al.  Clinical results of long-term treatment with a low protein diet and a new amino acid preparation in patients with chronic uremia. , 1983, Clinical nephrology.

[45]  S. Morrison.  Control of food intake in cancer cachexia: A challenge and a tool , 1976, Physiology & Behavior.