دورية أكاديمية
SIRT1-NOX4 signaling axis regulates cancer cachexia.
العنوان: | SIRT1-NOX4 signaling axis regulates cancer cachexia. |
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المؤلفون: | Dasgupta A; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE., Shukla SK; The Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE., Vernucci E; The Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE., King RJ; The Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE., Abrego J; The Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE., Mulder SE; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE., Mullen NJ; The Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE., Graves G; The Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE., Buettner K; The Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE., Thakur R; The Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE., Murthy D; The Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE., Attri KS; The Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE., Wang D; The Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE., Chaika NV; The Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE., Pacheco CG; The Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE., Rai I; The Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE., Engle DD; Cancer Center at Cold Spring Harbor Laboratory, Cold Spring Harbor, NY., Grandgenett PM; The Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE., Punsoni M; Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE., Reames BN; Department of Surgery, University of Nebraska Medical Center, Omaha, NE., Teoh-Fitzgerald M; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE., Oberley-Deegan R; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE., Yu F; Department of Biostatistics, University of Nebraska Medical Center, Omaha, NE., Klute KA; Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE., Hollingsworth MA; The Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE., Zimmerman MC; Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, NE., Mehla K; The Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE., Sadoshima J; Department of Cell Biology and Molecular Medicine, New Jersey Medical School, Rutgers University, Newark, NJ., Tuveson DA; Cancer Center at Cold Spring Harbor Laboratory, Cold Spring Harbor, NY., Singh PK; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE.; The Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE.; Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE. |
المصدر: | The Journal of experimental medicine [J Exp Med] 2020 Jul 06; Vol. 217 (7). |
نوع المنشور: | Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
اللغة: | English |
بيانات الدورية: | Publisher: Rockefeller University Press Country of Publication: United States NLM ID: 2985109R Publication Model: Print Cited Medium: Internet ISSN: 1540-9538 (Electronic) Linking ISSN: 00221007 NLM ISO Abbreviation: J Exp Med Subsets: MEDLINE |
أسماء مطبوعة: | Original Publication: New York, NY : Rockefeller University Press |
مواضيع طبية MeSH: | Signal Transduction*/drug effects, Cachexia/*complications , Cachexia/*metabolism , NADPH Oxidase 4/*metabolism , Neoplasms/*complications , Neoplasms/*metabolism , Sirtuin 1/*metabolism, Adipose Tissue/pathology ; Animals ; Cell Line ; Cell Line, Tumor ; Disease Models, Animal ; Disease Progression ; Forkhead Transcription Factors/metabolism ; HEK293 Cells ; Humans ; Metabolome/drug effects ; Mice ; Muscle Fibers, Skeletal/drug effects ; Muscle Fibers, Skeletal/metabolism ; Muscle, Skeletal/drug effects ; Muscle, Skeletal/metabolism ; Muscle, Skeletal/pathology ; Muscular Atrophy/metabolism ; Muscular Atrophy/pathology ; NF-kappa B/metabolism ; Oxidation-Reduction ; Pancreatic Neoplasms/metabolism ; Pancreatic Neoplasms/pathology ; Protein Stability/drug effects ; Reactive Oxygen Species/metabolism ; Resveratrol/pharmacology ; Wasting Syndrome/pathology |
مستخلص: | Approximately one third of cancer patients die due to complexities related to cachexia. However, the mechanisms of cachexia and the potential therapeutic interventions remain poorly studied. We observed a significant positive correlation between SIRT1 expression and muscle fiber cross-sectional area in pancreatic cancer patients. Rescuing Sirt1 expression by exogenous expression or pharmacological agents reverted cancer cell-induced myotube wasting in culture conditions and mouse models. RNA-seq and follow-up analyses showed cancer cell-mediated SIRT1 loss induced NF-κB signaling in cachectic muscles that enhanced the expression of FOXO transcription factors and NADPH oxidase 4 (Nox4), a key regulator of reactive oxygen species production. Additionally, we observed a negative correlation between NOX4 expression and skeletal muscle fiber cross-sectional area in pancreatic cancer patients. Knocking out Nox4 in skeletal muscles or pharmacological blockade of Nox4 activity abrogated tumor-induced cachexia in mice. Thus, we conclude that targeting the Sirt1-Nox4 axis in muscles is an effective therapeutic intervention for mitigating pancreatic cancer-induced cachexia. Competing Interests: Disclosures: D.A. Tuveson reported "other" from Surface Oncology, Leap Therapeutics, and Cygnal Therapeutics; grants from ONO and Fibrogen; personal fees from Chugai and Merck outside the submitted work; SAB, stock from Surface Oncology, Leap Therapeutics, and Cygnal Therapeutics; sponsored research from ONO and Fibrogen; and honoraria from Chugai and Merck. No other disclosures were reported. (© 2020 Dasgupta et al.) |
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معلومات مُعتمدة: | R01 CA216853 United States CA NCI NIH HHS; R01 CA188134 United States CA NCI NIH HHS; R01 HL091469 United States HL NHLBI NIH HHS; R01 CA190092 United States CA NCI NIH HHS; P30 CA036727 United States CA NCI NIH HHS; R01 CA163649 United States CA NCI NIH HHS; P30 CA045508 United States CA NCI NIH HHS; T32 CA009476 United States CA NCI NIH HHS; T32 CA148056 United States CA NCI NIH HHS; P01 CA217798 United States CA NCI NIH HHS; P50 CA127297 United States CA NCI NIH HHS; R50 CA211462 United States CA NCI NIH HHS; R01 CA210439 United States CA NCI NIH HHS; U01 CA210240 United States CA NCI NIH HHS; P30 GM103335 United States GM NIGMS NIH HHS; R01 HL112330 United States HL NHLBI NIH HHS |
المشرفين على المادة: | 0 (Forkhead Transcription Factors) 0 (NF-kappa B) 0 (Reactive Oxygen Species) EC 1.6.3.- (NADPH Oxidase 4) EC 3.5.1.- (Sirtuin 1) Q369O8926L (Resveratrol) |
تواريخ الأحداث: | Date Created: 20200523 Date Completed: 20210216 Latest Revision: 20210502 |
رمز التحديث: | 20221213 |
مُعرف محوري في PubMed: | PMC7336299 |
DOI: | 10.1084/jem.20190745 |
PMID: | 32441762 |
قاعدة البيانات: | MEDLINE |
تدمد: | 1540-9538 |
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DOI: | 10.1084/jem.20190745 |