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The Colon-26 Carcinoma Tumor-bearing Mouse as a Model for the Study of Cancer Cachexia
Published on: November 30, 2016
PEBP4 alleviates muscle wasting in lung cancer cachexia via KEAP1-NRF2-mediated redox homeostasis
Yaru Xia1, Yuqi Han2, Weiquan Li2
1Department of Pathogenic Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Abstract:
Cancer-associated cachexia (CAC) is a multifactorial metabolic syndrome characterized by progressive skeletal muscle wasting. However, the molecular link between tumor metabolic stress and muscle degradation remains elusive. Here, we identify phosphatidylethanolamine-binding protein 4 (PEBP4) as a key regulator of muscle homeostasis under cachectic conditions. PEBP4 expression is markedly suppressed in lung cachectic models and is inversely correlated with tumor-derived lactate levels. Mechanistically, PEBP4 stabilizes NRF2 by competitively binding to KEAP1, enhancing antioxidant defense, inhibiting NF-κB signaling, and downregulating muscle atrophy-related genes MuRF1 and Fbxo32 (also known as Atrogin-1). In vitro and in vivo overexpression of PEBP4 mitigates oxidative stress, preserves muscle mass, and improves strength and endurance in Lewis lung carcinoma tumor-bearing mice. These protective effects are significantly attenuated by NRF2 inhibition, highlighting its critical role in PEBP4-mediated signaling. Collectively, our findings uncover a tumor lactate-PEBP4-NRF2 axis linking cancer metabolism to redox imbalance and muscle wasting, and suggest the therapeutic potential of targeting the PEBP4-NRF2 pathway in lung cancer-associated cachexia.
Insights
Cancer-associated cachexia involves muscle wasting. Researchers found phosphatidylethanolamine-binding protein 4 (PEBP4) protects muscle by stabilizing NRF2, offering a new therapeutic target for lung cancer cachexia.
Area of Science:
- Oncology
- Metabolism
- Molecular Biology
Background:
- Cancer-associated cachexia (CAC) leads to severe muscle wasting.
- The molecular mechanisms linking tumor metabolism to muscle loss are not fully understood.
Purpose of the Study:
- To identify key regulators of muscle homeostasis in cancer-associated cachexia.
- To elucidate the molecular link between tumor metabolic stress and muscle degradation.
Main Methods:
- Investigated phosphatidylethanolamine-binding protein 4 (PEBP4) expression in lung cachexia models.
- Utilized in vitro and in vivo models to assess PEBP4's role in muscle homeostasis.
- Examined the interaction between PEBP4, KEAP1, and NRF2 signaling pathways.
Main Results:
- PEBP4 expression was suppressed in lung cachexia models and inversely correlated with tumor lactate.
- PEBP4 stabilizes NRF2, enhancing antioxidant defense and inhibiting muscle atrophy genes (MuRF1, Fbxo32).
- PEBP4 overexpression in tumor-bearing mice preserved muscle mass and function, effects dependent on NRF2.
Conclusions:
- Identified a tumor lactate-PEBP4-NRF2 axis linking cancer metabolism to muscle wasting.
- PEBP4 acts as a crucial regulator of muscle homeostasis by modulating redox balance.
- Targeting the PEBP4-NRF2 pathway shows therapeutic potential for lung cancer-associated cachexia.