Metastatic cancers promote cachexia through ZIP14 upregulation in skeletal muscle

Gang Wang; Anup K. Biswas; Wanchao Ma; Manoj Kandpal; Courtney Coker; Paul M. Grandgenett; Michael A. Hollingsworth; Rinku Jain; Kurenai Tanji; Sara López-Pintado; Alain Borczuk; Doreen Hebert; Supak Jenkitkasemwong; Shintaro Hojyo; Ramana V. Davuluri; Mitchell D. Knutson; Toshiyuki Fukada; Swarnali Acharyya

doi:10.1038/s41591-018-0054-2

Metastatic cancers promote cachexia through ZIP14 upregulation in skeletal muscle

Gang Wang, Anup K. Biswas, Wanchao Ma, Manoj Kandpal, Courtney Coker, Paul M. Grandgenett, Michael A. Hollingsworth, Rinku Jain, Kurenai Tanji, Sara López-Pintado, Alain Borczuk, Doreen Hebert, Supak Jenkitkasemwong, Shintaro Hojyo, Ramana V. Davuluri, Mitchell D. Knutson, Toshiyuki Fukada, Swarnali Acharyya

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124 Scopus citations

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.

Original language	English (US)
Pages (from-to)	770-781
Number of pages	12
Journal	Nature Medicine
Volume	24
Issue number	6
DOIs	https://doi.org/10.1038/s41591-018-0054-2
State	Published - Jun 1 2018

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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Wang, G., Biswas, A. K., Ma, W., Kandpal, M., Coker, C., Grandgenett, P. M., Hollingsworth, M. A., Jain, R., Tanji, K., López-Pintado, S., Borczuk, A., Hebert, D., Jenkitkasemwong, S., Hojyo, S., Davuluri, R. V., Knutson, M. D., Fukada, T., & Acharyya, S. (2018). Metastatic cancers promote cachexia through ZIP14 upregulation in skeletal muscle. Nature Medicine, 24(6), 770-781. https://doi.org/10.1038/s41591-018-0054-2

Wang, G, Biswas, AK, Ma, W, Kandpal, M, Coker, C, Grandgenett, PM, Hollingsworth, MA, Jain, R, Tanji, K, López-Pintado, S, Borczuk, A, Hebert, D, Jenkitkasemwong, S, Hojyo, S, Davuluri, RV, Knutson, MD, Fukada, T & Acharyya, S 2018, 'Metastatic cancers promote cachexia through ZIP14 upregulation in skeletal muscle', Nature Medicine, vol. 24, no. 6, pp. 770-781. https://doi.org/10.1038/s41591-018-0054-2

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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.",

author = "Gang Wang and Biswas, {Anup K.} and Wanchao Ma and Manoj Kandpal and Courtney Coker and Grandgenett, {Paul M.} and Hollingsworth, {Michael A.} and Rinku Jain and Kurenai Tanji and Sara L{\'o}pez-Pintado and Alain Borczuk and Doreen Hebert and Supak Jenkitkasemwong and Shintaro Hojyo and Davuluri, {Ramana V.} and Knutson, {Mitchell D.} and Toshiyuki Fukada and Swarnali Acharyya",

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AU - Wang, Gang

AU - Biswas, Anup K.

AU - Ma, Wanchao

AU - Kandpal, Manoj

AU - Coker, Courtney

AU - Grandgenett, Paul M.

AU - Hollingsworth, Michael A.

AU - Jain, Rinku

AU - Tanji, Kurenai

AU - López-Pintado, Sara

AU - Borczuk, Alain

AU - Hebert, Doreen

AU - Jenkitkasemwong, Supak

AU - Hojyo, Shintaro

AU - Davuluri, Ramana V.

AU - Knutson, Mitchell D.

AU - Fukada, Toshiyuki

AU - Acharyya, Swarnali

PY - 2018/6/1

Y1 - 2018/6/1

N2 - 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.

AB - 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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Metastatic cancers promote cachexia through ZIP14 upregulation in skeletal muscle

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