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Nat Med. 2018 Jun;24(6):770-781. doi: 10.1038/s41591-018-0054-2. Epub 2018 Jun 6.

Metastatic cancers promote cachexia through ZIP14 upregulation in skeletal muscle.

Author information

1
Institute for Cancer Genetics, Columbia University, New York, NY, USA.
2
Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
3
Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA.
4
Department of Structural & Chemical Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
5
Division of Neuropathology, Department of Pathology and Cell Biology, Columbia University Irving Medical Center and New York Presbyterian Hospital, New York, NY, USA.
6
Mailman School of Public Health, Columbia University, New York, NY, USA.
7
Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA.
8
Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY, USA.
9
Food Science and Human Nutrition Department, University of Florida, Gainesville, FL, USA.
10
Deutsches Rheuma-Forschungszentrum Berlin, Osteoimmunology, Berlin, Germany.
11
Molecular and Cellular Physiology, Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Tokushima, Japan.
12
Institute for Cancer Genetics, Columbia University, New York, NY, USA. sa3141@cumc.columbia.edu.
13
Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY, USA. sa3141@cumc.columbia.edu.
14
Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA. sa3141@cumc.columbia.edu.

Abstract

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.

PMID:
29875463
PMCID:
PMC6015555
DOI:
10.1038/s41591-018-0054-2
[Indexed for MEDLINE]
Free PMC Article

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