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      Metastatic cancers promote cachexia through altered zinc homeostasis in skeletal muscle


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          Metastatic cancer patients experience a severe loss of skeletal muscle mass and function known as cachexia. Cachexia is associated with poor prognosis and accelerated death in cancer patients, yet its underlying mechanisms remain poorly understood. Here, we identify the metal transporter ZIP14 as a critical mediator of cancer-induced cachexia. ZIP14 is upregulated in cachectic muscles from mice and patients with metastatic cancer and can be induced by TNF-α and TGF-β cytokines.

          Strikingly, in vivo manipulation of Zip14 expression has profound impact on muscle atrophy in experimental models of metastasis.

          We find that ZIP14-mediated zinc uptake in muscle progenitor cells represses the expression of the key myogenic factors 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 muscle during metastatic-cancer-induced cachexia, and implicate ZIP14 as a therapeutic target for its treatment.

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          Most cited references58

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          Cancer cachexia: mediators, signaling, and metabolic pathways.

          Cancer cachexia is characterized by a significant reduction in body weight resulting predominantly from loss of adipose tissue and skeletal muscle. Cachexia causes reduced cancer treatment tolerance and reduced quality and length of life, and remains an unmet medical need. Therapeutic progress has been impeded, in part, by the marked heterogeneity of mediators, signaling, and metabolic pathways both within and between model systems and the clinical syndrome. Recent progress in understanding conserved, molecular mechanisms of skeletal muscle atrophy/hypertrophy has provided a downstream platform for circumventing the variations and redundancy in upstream mediators and may ultimately translate into new targeted therapies. Copyright © 2012 Elsevier Inc. All rights reserved.
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            The tumour-induced systemic environment as a critical regulator of cancer progression and metastasis.

            Recent pre-clinical and clinical research has provided evidence that cancer progression is driven not only by a tumour's underlying genetic alterations and paracrine interactions within the tumour microenvironment, but also by complex systemic processes. We review these emerging paradigms of cancer pathophysiology and discuss how a clearer understanding of systemic regulation of cancer progression could guide development of new therapeutic modalities and efforts to prevent disease relapse following initial diagnosis and treatment.
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              IKKbeta/NF-kappaB activation causes severe muscle wasting in mice.

              Muscle wasting accompanies aging and pathological conditions ranging from cancer, cachexia, and diabetes to denervation and immobilization. We show that activation of NF-kappaB, through muscle-specific transgenic expression of activated IkappaB kinase beta (MIKK), causes profound muscle wasting that resembles clinical cachexia. In contrast, no overt phenotype was seen upon muscle-specific inhibition of NF-kappaB through expression of IkappaBalpha superrepressor (MISR). Muscle loss was due to accelerated protein breakdown through ubiquitin-dependent proteolysis. Expression of the E3 ligase MuRF1, a mediator of muscle atrophy, was increased in MIKK mice. Pharmacological or genetic inhibition of the IKKbeta/NF-kappaB/MuRF1 pathway reversed muscle atrophy. Denervation- and tumor-induced muscle loss were substantially reduced and survival rates improved by NF-kappaB inhibition in MISR mice, consistent with a critical role for NF-kappaB in the pathology of muscle wasting and establishing it as an important clinical target for the treatment of muscle atrophy.

                Author and article information

                Nat Med
                Nat. Med.
                Nature medicine
                30 March 2018
                06 June 2018
                June 2018
                06 December 2018
                : 24
                : 6
                : 770-781
                [1 ]Institute for Cancer Genetics, Columbia University, New York, NY 10032, USA
                [2 ]Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
                [3 ]Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA
                [4 ]Department of Structural & Chemical Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
                [5 ]Division of Neuropathology, Department of Pathology and Cell Biology, Columbia University Irving Medical Center and New York Presbyterian Hospital, New York, NY 10032, USA
                [6 ]Mailman School of Public Health, Columbia University, New York, NY 10032, USA
                [7 ]Department of Pathology, Weill Cornell Medicine, New York, NY 10065, USA
                [8 ]Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY 10032, USA
                [9 ]Food Science and Human Nutrition Department, University of Florida, Gainesville, FL 32611, USA
                [10 ]Deutsches Rheuma-Forschungszentrum Berlin, Osteoimmunology, Charitéplatz, Berlin, Germany
                [11 ]Molecular and Cellular Physiology, Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Yamashiro, Tokushima, Japan
                [12 ]Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032, USA
                Author notes
                Correspondence: Swarnali Acharyya, Ph.D. 1130 St. Nicholas Avenue, Room, 402B New York, NY 10032 USA, Tel.: +1 212-851-4792; sa3141@ 123456cumc.columbia.edu

                G.W., A.K.B. and W.M. contributed equally to this work.


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