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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gp130 via the JAK/STAT pathway mediates muscle atrophy in a cancer cachexia mouse model.
“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]
The Abstract and Discussion (page unavailable) report that Stat3 activation contributes to muscle loss in mice with C26 or Lewis lung carcinoma tumors, and that inhibiting Stat3 preserves muscle mass. The paper does not establish that gp130 mediates this effect; gp130 appears in the title of a cited work in the References, not as a tested mediator in this study. (LLM, conf=0.88)
Experimental — accuracy not yet measuredInhibition of STAT3 with TTI-101 reverses muscle loss in cachexia models by suppressing MAFbx/Atrogin-1 and MuRF1 expression and reducing caspase-3 activity.
“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
The Experimental Procedures and Discussion identify the inhibitor used as C188-9, not TTI-101; our copy does not establish that the names refer to the same compound. The paper reports that C188-9 preserved muscle mass in C26 tumor-bearing mice, reduced MAFbx/Atrogin-1 and MuRF-1 expression, and blocked a marker of caspase-3 proteolytic activity. The LLC model used muscle-specific Stat3 knockout rather than inhibitor treatment, so the claim that the named drug reversed muscle loss in both models is not supported. (LLM, conf=0.90)
Experimental — accuracy not yet measuredIL-6/STAT3 signaling is linked to muscle and adipose tissue wasting in mouse models of cachexia and has preliminary reinforcement in clinical studies.
“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
The mouse experiments and Discussion support a link between STAT3 signaling and muscle wasting in cancer cachexia; the Discussion proposes IL-6 as one possible activator. The introductory passage reports mouse studies of IL-6-associated muscle and fat loss, but also calls those results controversial. It does not establish STAT3-mediated adipose wasting, and the cited paper provides no clinical evidence for the separate clause about clinical studies. (LLM, conf=0.85)
Experimental — accuracy not yet measuredLevels of pY-STAT3 are increased in skeletal muscle in mouse models of cachexia, including chronic kidney disease and cancer.
“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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Stat3 activation induces insulin resistance via a muscle-specific E3 ubiquitin ligase Fbxo40
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The Redox Balance: A Target for Interventions Against Muscle Wasting in Cancer Cachexia?
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Self-citationA Pound of Flesh: What Cachexia Is and What It Is Not
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Muscle wasting: emerging pathways and potential drug targets
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Regulation of Skeletal Muscle DRP-1 and FIS-1 Protein Expression by IL-6 Signaling
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- 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 · 2014: 1
- 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 › Nutrition and Health in Aging
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › 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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