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Inhibition of Stat3 Activation Suppresses Caspase-3 and the Ubiquitin-Proteasome System, Leading to Preservation of Muscle Mass in Cancer Cachexia
Open accessAbstract
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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“Our data are in accordance with previous reports showing that gp130 via the JAK/STAT pathway mediates muscle atrophy in a cancer cachexia mouse model. 15 , 27 , 28”
From Sepsis induces interleukin 6, gp130/JAK2/STAT3, and muscle wasting (2022) · cites this paper as [28]
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“Inhibition of STAT3 with TTI-101 reversed muscle loss in both cachexia models by suppressing the expression of MAFbx/Atrogin-1 and MuRF1 and reducing caspase-3 activity”
From Targeting Janus Kinases and Signal Transducer and Activator of Transcription 3 To Treat Inflammation, Fibrosis, and Cancer: Rationale, Progress, and Caution (2020) · cites this paper as Silva et al., 2015
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“The link between IL-6/STAT3 signaling and muscle and adipose tissue wasting is well established in mouse models of cachexia (White et al., 2011; Silva et al., 2015) and has been reinforced preliminarily in clinical studies.”
From Targeting Janus Kinases and Signal Transducer and Activator of Transcription 3 To Treat Inflammation, Fibrosis, and Cancer: Rationale, Progress, and Caution (2020) · cites this paper as Silva et al., 2015
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“Levels of pY-STAT3 are increased in skeletal muscle in mouse models of cachexia, including models of chronic kidney disease (Zhang et al., 2013a) and cancer (Silva et al., 2015).”
From Targeting Janus Kinases and Signal Transducer and Activator of Transcription 3 To Treat Inflammation, Fibrosis, and Cancer: Rationale, Progress, and Caution (2020) · cites this paper as Silva et al., 2015
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Identification of ubiquitin ligases required for skeletal muscle atrophy.
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Self-citationTisdale, M. J. (2009) · Physiological Reviews · doi:10.1152/physrev.00016.2008 · Cited by 1,216
Mechanisms of Muscle Wasting — The Role of the Ubiquitin–Proteasome Pathway
Mitch, W. E., & Goldberg, A. L. (1996) · New England Journal of Medicine · doi:10.1056/nejm199612193352507 · Cited by 1,163
Self-citationTisdale, M. J. (2002) · Nature reviews. Cancer · doi:10.1038/nrc927 · Cited by 993
Reversal of Cancer Cachexia and Muscle Wasting by ActRIIB Antagonism Leads to Prolonged Survival
Zhou, X., Wang, J. L., Lu, J., Song, Y., Kwak, K. S., Jiao, Q., Rosenfeld, R., Chen, Q., Boone, T. C., Simonet, W. S., et al. (2010) · Cell · doi:10.1016/j.cell.2010.07.011 · Cited by 960
Du, J., Wang, X., Miereles, C., Bailey, J. L., Debigaré, R., Zheng, B., Price, S. R., & Mitch, W. E. (2004) · Journal of Clinical Investigation · doi:10.1172/jci18330 · Cited by 730
Self-citationPathophysiologic Response to Severe Burn Injury
Jeschke, M. G., Chinkes, D. L., Finnerty, C. C., Kulp, G. A., Suman-Vejas, O. E., Norbury, W. B., Branski, L. K., Gauglitz, G. G., Mlcak, R. P., & Herndon, D. N. (2008) · Annals of Surgery · doi:10.1097/sla.0b013e3181856241 · Cited by 719
Wang, X., Hu, Z., Hu, J., Du, J., & Mitch, W. E. (2006) · Endocrinology · doi:10.1210/en.2006-0251 · Cited by 600
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Baracos, V. E., Martin, L., Korc, M., Guttridge, D. C., & Fearon, K. C. H. (2018) · Nature Reviews Disease Primers · doi:10.1038/nrdp.2017.105 · Cited by 1,738
Paradoxical roles of caspase-3 in regulating cell survival, proliferation, and tumorigenesis
Eskandari, E., & Eaves, C. J. (2022) · The Journal of Cell Biology · doi:10.1083/jcb.202201159 · Cited by 504
Skeletal muscle atrophy: From mechanisms to treatments
Yin, L., Li, N., Jia, W., Wang, N., Liang, M., Yang, X., & Du, G. (2021) · Pharmacological Research · doi:10.1016/j.phrs.2021.105807 · Cited by 423
Inflammation and Skeletal Muscle Wasting During Cachexia
Webster, J. M., Kempen, L. J. A. P., Hardy, R. S., & Langen, R. C. J. (2020) · Frontiers in Physiology · doi:10.3389/fphys.2020.597675 · Cited by 372
Cancer cachexia: molecular mechanisms and treatment strategies
Setiawan, T., Sari, I. N., Wijaya, Y. T., Julianto, N. M., Muhammad, J. A., Lee, H., Chae, J. H., & Kwon, H. Y. (2023) · Journal of Hematology & Oncology · doi:10.1186/s13045-023-01454-0 · Cited by 342
Metadata
- Authors
- Silva, K. A. S., Dong, J., Dong, Y., Dong, Y., Schor, N., Tweardy, D. J., Zhang, L., & Mitch, W. E.
- Affiliations
- Universidade Federal de São Paulo (BR)
- Sichuan University (CN)
- Capital Medical University (CN)
- Baylor College of Medicine (US)
- Corresponding author
- Zhang, Liping
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2015-04
- Volume
- 290
- Issue
- 17
- Pages
- 11177-11187
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC4409274
- OpenAlex
- W2011567765
- Cited by
- 229
- References
- 52
- Citations by year
- 2026: 9 · 2025: 18 · 2024: 20 · 2023: 23 · 2022: 35 · 2021: 25 · 2020: 27 · 2019: 17 · 2018: 17 · 2017: 16 · 2016: 16 · 2015: 4
- FWCI
- 7.67
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- UNIFESP Institutional Repository (Universidade Federal de São Paulo) (submittedVersion)
- Funders
- National Institutes of Health (R37 DK37175, P50 CA058183, P50 CA097007, R21 CA149783)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Health Sciences › Medicine › Physiology (medical) › Nutrition and Health in Aging
- Health Sciences › Nursing › Nutrition and Dietetics › Muscle metabolism and nutrition
- Keywords
- cancer cachexia, STAT3 activation, caspase-3, ubiquitin-proteasome system, C/EBPδ, myostatin, atrogin-1/MAFbx, MuRF1, muscle protein degradation, muscle mass preservation, JAK/STAT signaling, Lewis lung carcinoma, C26 colon carcinoma, muscle protein synthesis
- MeSH terms
- Tripartite Motif Proteins, Animals, Cachexia, Colonic Neoplasms, Muscle Proteins, Mice, Knockout, Muscle, Skeletal, Carcinoma, Lewis Lung, Ubiquitin, Ubiquitin-Protein Ligases, SKP Cullin F-Box Protein Ligases, Cell Line, Tumor, Proteasome Endopeptidase Complex, STAT3 Transcription Factor, Mice, CCAAT-Enhancer-Binding Protein-delta, Caspase 3, Myostatin, Proteolysis
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