title: Inhibition of Stat3 activation suppresses caspase-3 and the ubiquitin-proteasome system, leading to preservation of muscle mass in cancer cachexia.
abstract: 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 medium from C26 colon carcinoma (C26) or Lewis lung carcinoma cells activates 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 CAAT/enhancer-binding protein δ (C/EBPδ). Using sequential deletions of the caspase-3 promoter and CHIP assays, we determined that Stat3 activation increases caspase-3 expression in C2C12 cells. Caspase-3 expression and proteolytic activity were stimulated by p-Stat3 in muscles of tumor-bearing mice. In mice with cachexia caused by Lewis lung carcinoma or C26 tumors, knock-out of p-Stat3 in muscle or with a small chemical inhibitor of p-Stat3 suppressed muscle mass losses, improved protein synthesis and degradation in muscle, and increased body weight and grip strength. Activation of p-Stat3 stimulates a pathway from C/EBPδ to myostatin and expression of MAFbx/Atrogin-1 and increases the ubiquitin-proteasome system. Indeed, C/EBPδ KO decreases the expression of MAFbx/Atrogin-1 and myostatin, while increasing muscle mass and grip strength. In conclusion, cancer stimulates p-Stat3 in muscle, activating protein loss by stimulating caspase-3, myostatin, and the ubiquitin-proteasome system. These results could lead to novel strategies for preventing cancer-induced muscle wasting.
authors: From the Nephrology Division, Department of Medicine, and the Nephrology Division, Department of Medicine, Federal University of Sao Paulo, Sao Paulo 04023-900, Brazil.
authors: Kleiton Augusto Santos
authors: KA
authors: Silva
authors: From the Nephrology Division, Department of Medicine, and the College of Life Sciences, Sichuan University, Chengdu 610065, China, and.
authors: Jiangling
authors: J
authors: Dong
authors: From the Nephrology Division, Department of Medicine, and the Beijing Institute of Heart, Lung, and Blood Vessel Diseases, An Zhen Hospital Affiliated to Capital Medical University, Beijing 100029, China.
authors: Yanjun
authors: Y
authors: Dong
authors: From the Nephrology Division, Department of Medicine, and.
authors: Yanlan
authors: Y
authors: Dong
authors: the Nephrology Division, Department of Medicine, Federal University of Sao Paulo, Sao Paulo 04023-900, Brazil.
authors: Nestor
authors: N
authors: Schor
authors: the Departments of Medicine (Section of Infectious Diseases), Molecular and Cellular Biology, and Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas 77030.
authors: David J
authors: DJ
authors: Tweardy
authors: From the Nephrology Division, Department of Medicine, and lipingz@bcm.edu.
authors: Liping
authors: L
authors: Zhang
authors: From the Nephrology Division, Department of Medicine, and.
authors: William E
authors: WE
authors: Mitch
mesh_terms: D000818:Animals; D051743:CCAAT-Enhancer-Binding Protein-delta / Q000235:genetics / Q000378:metabolism; D002100:Cachexia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018827:Carcinoma, Lewis Lung / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology; D055435:Myostatin / Q000235:genetics / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism*; D059748:Proteolysis; D044843:SKP Cullin F-Box Protein Ligases / Q000235:genetics / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D000070584:Tripartite Motif Proteins; D025801:Ubiquitin / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism
chemical_list: C497253:Cebpd protein, mouse; D009124:Muscle Proteins; D055435:Myostatin; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D000070584:Tripartite Motif Proteins; D025801:Ubiquitin; D051743:CCAAT-Enhancer-Binding Protein-delta; C486691:Fbxo32 protein, mouse; D044843:SKP Cullin F-Box Protein Ligases; C499084:Trim63 protein, mouse; D044767:Ubiquitin-Protein Ligases; C505409:Casp3 protein, mouse; D053148:Caspase 3; D046988:Proteasome Endopeptidase Complex
keywords: Cancer Biology; Cancer Cachexia; Caspase; Caspase-3; Muscle Atrophy; STAT3; Ubiquitin