Metastatic cancers promote cachexia through ZIP14 upregulation in skeletal muscle

Metastatic cancers promote cachexia through ZIP14 upregulation in skeletal muscle 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. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Nature Medicine Springer Journals

Metastatic cancers promote cachexia through ZIP14 upregulation in skeletal muscle

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Publisher
Springer Journals
Copyright
Copyright © 2018 by The Author(s)
Subject
Biomedicine; Biomedicine, general; Cancer Research; Metabolic Diseases; Infectious Diseases; Molecular Medicine; Neurosciences
ISSN
1078-8956
eISSN
1546-170X
DOI
10.1038/s41591-018-0054-2
Publisher site
See Article on Publisher Site

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.

Journal

Nature Medicine – Springer Journals

Published: Jun 6, 2018

References

  • Emerging biological principles of metastasis
    Lambert, AW; Pattabiraman, DR; Weinberg, RA
  • Metastatic colonization by circulating tumour cells
    Massagué, J; Obenauf, AC
  • Excess TGF-β mediates muscle weakness associated with bone metastases in mice
    Waning, DL
  • Extracellular vesicles in cancer: cell-to-cell mediators of metastasis
    Becker, A
  • The tumour-induced systemic environment as a critical regulator of cancer progression and metastasis
    McAllister, SS; Weinberg, RA
  • Cancer cachexia: understanding the molecular basis
    Argilés, JM; Busquets, S; Stemmler, B; López-Soriano, FJ
  • Cancer cachexia: mediators, signaling, and metabolic pathways
    Fearon, KC; Glass, DJ; Guttridge, DC
  • Understanding the mechanisms and treatment options in cancer cachexia
    Fearon, K; Arends, J; Baracos, V
  • Cancer-associated cachexia
    Baracos, VE; Martin, L; Korc, M; Guttridge, DC; Fearon, KCH
  • Muscle wasting in disease: molecular mechanisms and promising therapies
    Cohen, S; Nathan, JA; Goldberg, AL
  • Protein breakdown in cancer cachexia
    Sandri, M
  • Experimental cancer cachexia: evolving strategies for getting closer to the human scenario
    Penna, F; Busquets, S; Argilés, JM
  • Prognostic effect of weight loss prior to chemotherapy in cancer patients
    Dewys, WD
  • The multiple faces of the metal transporter ZIP14 (SLC39A14)
    Aydemir, TB; Cousins, RJ
  • Transition metal speciation in the cell: insights from the chemistry of metal ion receptors
    Finney, LA; O’Halloran, TV
  • Mammalian zinc transporters: nutritional and physiologic regulation
    Lichten, LA; Cousins, RJ
  • Trace element changes in serum and skeletal muscle compared to tumour tissue in sarcoma-bearing rats
    Larsson, S; Karlberg, I; Selin, E; Daneryd, P; Peterson, HI
  • Systemic zinc redistribution and dyshomeostasis in cancer cachexia
    Siren, PM; Siren, MJ
  • Enhanced metastatic potential of tumor cells harvested from spontaneous metastases of heterogeneous murine tumors
    Talmadge, JE; Fidler, IJ
  • Mouse models of advanced spontaneous metastasis for experimental therapeutics
    Francia, G; Cruz-Munoz, W; Man, S; Xu, P; Kerbel, RS
  • Cancer cachexia: developing multimodal therapy for a multidimensional problem
    Fearon, KC
  • The prognosis of acute respiratory failure in critically ill cancer patients
    Azoulay, E
  • Involvement of parathyroid hormone–related protein in experimental cachexia induced by a human lung cancer–derived cell line established from a bone metastasis specimen
    Iguchi, H; Onuma, E; Sato, K; Sato, K; Ogata, E
  • Cardiac and skeletal muscles show molecularly distinct responses to cancer cachexia
    Shum, AM
  • STAT3 activation in skeletal muscle links muscle wasting and the acute phase response in cancer cachexia
    Bonetto, A
  • Mouse models for lung cancer
    Kwon, MC; Berns, A
  • WNT/TCF signaling through LEF1 and HOXB9 mediates lung adenocarcinoma metastasis
    Nguyen, DX
  • Loss of Lkb1 and Pten leads to lung squamous cell carcinoma with elevated PD-L1 expression
    Xu, C
  • TNF-α in promotion and progression of cancer
    Balkwill, F
  • IKKβ/NF-κβ activation causes severe muscle wasting in mice
    Cai, D
  • NF-κβ-induced loss of MyoD messenger RNA: possible role in muscle decay and cachexia
    Guttridge, DC; Mayo, MW; Madrid, LV; Wang, CY; Baldwin, AS
  • The zinc transporter SLC39A14/ZIP14 controls G-protein coupled receptor–mediated signaling required for systemic growth
    Hojyo, S
  • Interleukin-6 regulates the zinc transporter Zip14 in liver and contributes to the hypozincemia of the acute-phase response
    Liuzzi, JP
  • NF-κB-mediated Pax7 dysregulation in the muscle microenvironment promotes cancer cachexia
    He, WA
  • The molecular regulation of myogenesis
    Sabourin, LA; Rudnicki, MA
  • Muscle wasting and impaired myogenesis in tumor bearing mice are prevented by ERK inhibition
    Penna, F
  • Requirement of MEF2A, C, and D for skeletal muscle regeneration
    Liu, N
  • Inhibition of myogenic differentiation in proliferating myoblasts by cyclin D1-dependent kinase
    Skapek, SX; Rhee, J; Spicer, DB; Lassar, AB
  • Regulation of MyoD function in the dividing myoblast
    Wei, Q; Paterson, BM
  • Signaling pathways perturbing muscle mass
    Glass, DJ
  • Diaphragm and ventilatory dysfunction during cancer cachexia
    Roberts, BM
  • During muscle atrophy, thick, but not thin, filament components are degraded by MuRF1-dependent ubiquitylation
    Cohen, S
  • The E3 ligase MuRF1 degrades myosin heavy chain protein in dexamethasone-treated skeletal muscle
    Clarke, BA
  • Cancer cachexia is regulated by selective targeting of skeletal muscle gene products
    Acharyya, S
  • Serum and tissue trace elements in colorectal cancer
    Gupta, SK; Shukla, VK; Vaidya, MP; Roy, SK; Gupta, S
  • The role of zinc in the anti-tumour and anti-cachectic activity of d-myo-inositol 1,2,6-triphosphate
    Russell, ST; Siren, PM; Siren, MJ; Tisdale, MJ
  • Tissue-specific regulation of zinc metabolism and metallothionein genes by interleukin 1
    Cousins, RJ; Leinart, AS
  • Blockade of metallothioneins 1 and 2 increases skeletal muscle mass and strength
    Summermatter, S
  • Excessive intracellular zinc accumulation in cardiac and skeletal muscles of dystrophic hamsters
    Crawford, AJ; Bhattacharya, SK
  • Multiple types of skeletal muscle atrophy involve a common program of changes in gene expression
    Lecker, SH
  • Breast cancer bone metastasis mediated by the Smad tumor suppressor pathway
    Kang, Y
  • Mechanisms regulating skeletal muscle growth and atrophy
    Schiaffino, S; Dyar, KA; Ciciliot, S; Blaauw, B; Sandri, M
  • Increased expression of phosphorylated forms of RNA-dependent protein kinase and eukaryotic initiation factor 2α may signal skeletal muscle atrophy in weight-losing cancer patients
    Eley, HL; Skipworth, RJ; Deans, DA; Fearon, KC; Tisdale, MJ
  • Activity of the Akt-dependent anabolic and catabolic pathways in muscle and liver samples in cancer-related cachexia
    Schmitt, TL
  • Zinc is a novel intracellular second messenger
    Yamasaki, S
  • Metalloproteomes: a bioinformatic approach
    Andreini, C; Bertini, I; Rosato, A
  • Intrinsic and extrinsic mechanisms regulating satellite cell function
    Dumont, NA; Wang, YX; Rudnicki, MA
  • Impaired regeneration: a role for the muscle microenvironment in cancer cachexia
    Talbert, EE; Guttridge, DC
  • Mechanisms of muscle degeneration, regeneration, and repair in the muscular dystrophies
    Wallace, GQ; McNally, EM
  • A drug repositioning approach identifies tricyclic antidepressants as inhibitors of small cell lung cancer and other neuroendocrine tumors
    Jahchan, NS
  • Dystrophin glycoprotein complex dysfunction: a regulatory link between muscular dystrophy and cancer cachexia
    Acharyya, S
  • Global secretome analysis identifies novel mediators of bone metastasis
    Blanco, MA
  • Muscle actin is polyubiquitinylated in vitro and in vivo and targeted for breakdown by the E3 ligase MuRF1
    Polge, C
  • Detection and imaging of zinc secretion from pancreatic β-cells using a new fluorescent zinc indicator
    Gee, KR; Zhou, ZL; Qian, WJ; Kennedy, R
  • Immunocytochemical localization of secreted transforming growth factor-β1 to the advancing edges of primary tumors and to lymph node metastases of human mammary carcinoma
    Dalal, BI; Keown, PA; Greenberg, AH
  • slc39a14 is required for the development of hepatocellular iron overload in murine models of hereditary hemochromatosis
    Jenkitkasemwong, S
  • Health evaluation of experimental laboratory mice
    Burkholder, T; Foltz, C; Karlsson, E; Linton, CG; Smith, JM
  • Conditional mouse lung cancer models using adenoviral or lentiviral delivery of Cre recombinase
    DuPage, M; Dooley, AL; Jacks, T
  • Zinc sulphate induces metallothionein in pancreatic islets of mice and protects against diabetes induced by multiple low doses of streptozotocin
    Ohly, P; Dohle, C; Abel, J; Seissler, J; Gleichmann, H
  • Rapid, scalable, and low-cost purification of recombinant adeno-associated virus produced by baculovirus expression vector system
    Buclez, PO
  • Isolation, culture, functional assays, and immunofluorescence of myofiber-associated satellite cells
    Vogler, TO; Gadek, KE; Cadwallader, AB; Elston, TL; Olwin, BB
  • Isolation, culture, and transplantation of muscle satellite cells
    Motohashi, N; Asakura, Y; Asakura, A
  • A CXCL1 paracrine network links cancer chemoresistance and metastasis
    Acharyya, S
  • Analysis of relative gene expression data using real-time quantitative PCR and the 2–ΔΔCT method
    Livak, KJ; Schmittgen, TD
  • Myofibril breakdown during atrophy is a delayed response requiring the transcription factor PAX4 and desmin depolymerization
    Volodin, A; Kosti, I; Goldberg, AL; Cohen, S
  • Myosin heavy chain is not selectively decreased in murine cancer cachexia
    Cosper, PF; Leinwand, LA
  • The Molecular Signatures Database (MSigDB) hallmark gene set collection
    Liberzon, A
  • Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles
    Subramanian, A

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