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Metastatic cancers promote cachexia through ZIP14 upregulation in skeletal muscle
Open accessAbstract
Patients with metastatic cancer experience a severe loss of skeletal muscle mass and function known as cachexia. Cachexia is associated with poor prognosis and accelerated death in patients with cancer, yet its underlying mechanisms remain poorly understood. Here, we identify the metal-ion transporter ZRT- and IRT-like protein 14 (ZIP14) as a critical mediator of cancer-induced cachexia. ZIP14 is upregulated in cachectic muscles of mice and in patients with metastatic cancer and can be induced by TNF-α and TGF-β cytokines. Strikingly, germline ablation or muscle-specific depletion of Zip14 markedly reduces muscle atrophy in metastatic cancer models. We find that ZIP14-mediated zinc uptake in muscle progenitor cells represses the expression of MyoD and Mef2c and blocks muscle-cell differentiation. Importantly, ZIP14-mediated zinc accumulation in differentiated muscle cells induces myosin heavy chain loss. These results highlight a previously unrecognized role for altered zinc homeostasis in metastatic cancer-induced muscle wasting and implicate ZIP14 as a therapeutic target for its treatment.
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“Conversely, the increase of the metal-ion transporter ZRT- and IRT-like protein 14 (ZIP14), which controls the uptake of Zn ions, has been shown to promote muscle loss. ZIP14 is upregulated by TNF-α and TGF-β cytokines and ZIP14-dependent zinc accumulation induces myosin heavy chain loss, while muscle-specific deletion of ZIP14 prevents muscle loss in tumor-bearing mice30.”
From Mechanisms of muscle atrophy and hypertrophy: implications in health and disease (2021) · cites this paper as [30]
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Mechanisms of muscle atrophy and hypertrophy: implications in health and disease
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Tumour extracellular vesicles and particles induce liver metabolic dysfunction
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Self-citationCachexia: A systemic consequence of progressive, unresolved disease
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Cancer Cachexia: More Than Skeletal Muscle Wasting
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Metadata
- Authors
- Wang, G., Biswas, A. K., Ma, W., Kandpal, M., Coker, C., Grandgenett, P. M., Hollingsworth, M. A., Jain, R., Tanji, K., Lόpez-Pintado, S., Borczuk, A., Hebert, D., Jenkitkasemwong, S., Hojyo, S., Davuluri, R. V., Knutson, M. D., Fukada, T., & Acharyya, S.
- Affiliations
- Columbia University (US)
- Northwestern University (US)
- Fred and Pamela Buffett Cancer Center (US)
- Icahn School of Medicine at Mount Sinai (US)
- NewYork–Presbyterian Hospital (US)
- Weill Cornell Medicine (US)
- Columbia University Irving Medical Center (US)
- University of Florida (US)
- German Rheumatism Research Centre (DE)
- Tokushima Bunri University (JP)
- Corresponding author
- Acharyya, Swarnali
- ORCID
- Venue
- Nature Medicine
- Published
- 2018-06
- Volume
- 24
- Issue
- 6
- Pages
- 770-781
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- PMC
- PMC6015555
- OpenAlex
- W2805831922
- Cited by
- 188
- References
- 83
- Citations by year
- 2026: 17 · 2025: 29 · 2024: 21 · 2023: 22 · 2022: 30 · 2021: 22 · 2020: 23 · 2019: 19 · 2018: 5
- FWCI
- 6.19
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Nature Medicine (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Japan Society for the Promotion of Science (17H04011)
- National Cancer Institute (P50CA127297, R00CA172697, U01CA210240, P30CA013696, R50CA211462)
- National Institute of Diabetes and Digestive and Kidney Diseases (R56DK080706, R01DK080706)
- U.S. National Library of Medicine (R01LM011297)
- 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 › Trace Elements in Health
- Keywords
- cancer cachexia, metastatic cancer, ZIP14, zinc homeostasis, skeletal muscle atrophy, muscle atrophy, zinc uptake, muscle progenitor cells, MyoD, MEF2C, myosin heavy chain, TNF-α, TGF-beta, therapeutic target
- MeSH terms
- Animals, Cachexia, Cell Differentiation, Cell Line, Disease Models, Animal, Humans, Mice, Inbred C57BL, Neoplasm Metastasis, Neoplasms, Tumor Necrosis Factor-alpha, Zinc, Up-Regulation, Cytokines, Transforming Growth Factor beta, Muscle, Skeletal, Myosin Heavy Chains, Cation Transport Proteins
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