ArticleThe Journal of biological chemistry2015
Inhibition of Stat3 activation suppresses caspase-3 and the ubiquitin-proteasome system, leading to preservation of muscle mass in cancer cachexia.
Article in The Journal of biological chemistry, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 133 papers.
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Who cites it
133 citing papers in PubMed, 223 citations in OpenAlex.
- JAK inhibition with tofacitinib rapidly increases contractile force in human skeletal muscle.Life science alliance · 2024Trial
- Tumor-Secreted ADAMTSL4 Activates Latent TGFβ1 to Drive Cancer Cachexia.Cancer discovery · 2026Article
- Li-ginseng powder alleviates cancer cachexia in mice by regulating the ubiquitin-proteasome pathway and reducing inflammation.Journal of ginseng research · 2026Article
- Long-chain Polyunsaturated Fatty Acids MitigatebioRxiv : the preprint server for biology · 2026Article
- Cancer cachexia: molecular basis and therapeutic advances.Signal transduction and targeted therapy · 2026Review
- Sepsis-associated skeletal muscle wasting is ameliorated by pharmacological inhibition of the STAT3 signaling pathway in mice.Scientific reports · 2026Article
- Cancer cachexia as an immunometabolic syndrome: targeting the immunometabolic interface with traditional Chinese Medicine monomers and formulas.Frontiers in immunology · 2026Review
- The canonical ER stress IRE1α/XBP1 pathway mediates skeletal muscle wasting during pancreatic cancer cachexia.EMBO molecular medicine · 2025Article
- Association of serological biomarkers with muscle strength and function in sarcopenia: a cross-sectional study.Annals of medicine · 2025Article
- STAT3 Inhibition to Treat Ulcerative Colitis-Associated Colorectal Cancer.International journal of molecular sciences · 2025Article
- JAK1/2 Inhibition Delays Cachexia and Improves Survival through Increased Food Intake.bioRxiv : the preprint server for biology · 2025Article
- Signaling networks governing skeletal muscle growth, atrophy, and cachexiaSkeletal muscle · 2025Review
- Sarcopenia: Current Insights into Molecular Mechanisms, Diagnostics, and Emerging Interventional Approaches.International journal of molecular sciences · 2025Review
- Functions and Therapeutic Potentials of Long Noncoding RNA in Skeletal Muscle Atrophy and Dystrophy.Journal of cachexia, sarcopenia and muscle · 2025Review
- Tomatidine Attenuates Inflammatory Responses to Exercise-Like Stimulation in Donor-derived Skeletal Muscle Myobundles.Medical research archives · 2025Article
- Basic biology and roles of CEBPD in cardiovascular disease.Cell death discovery · 2025Review
- Probing the Depths of Molecular Complexity: STAT3 as a Key Architect in Colorectal Cancer Pathogenesis.Current gene therapy · 2025Review
- Cancer Cachexia.Advances in experimental medicine and biology · 2025Review
- Unraveling the role of STAT3 in Cancer Cachexia: pathogenic mechanisms and therapeutic opportunities.Frontiers in endocrinology · 2025Review
- Article
73 more citing papers are in PubMed but not listed here.
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Authors and funding
8 authors at 4 institutions in 3 countries.
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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.
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