دورية أكاديمية
أعرض في EDS

BRAFV600E-Driven Lung Adenocarcinoma Requires Copper to Sustain Autophagic Signaling and Processing.

التفاصيل البيبلوغرافية
العنوان: BRAFV600E-Driven Lung Adenocarcinoma Requires Copper to Sustain Autophagic Signaling and Processing.
المؤلفون: Tsang T; Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.; Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.; Cell and Molecular Biology Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania., Gu X; Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.; Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania., Davis CI; Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.; Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.; Biochemistry and Molecular Biophysics Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania., Posimo JM; Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.; Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania., Miller ZA; Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.; Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.; Pharmacology Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania., Brady DC; Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.; Cell and Molecular Biology Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
المصدر: Molecular cancer research : MCR [Mol Cancer Res] 2022 Jul 06; Vol. 20 (7), pp. 1096-1107.
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't; Research Support, N.I.H., Extramural
اللغة: English
بيانات الدورية: Publisher: American Association for Cancer Research Country of Publication: United States NLM ID: 101150042 Publication Model: Print Cited Medium: Internet ISSN: 1557-3125 (Electronic) Linking ISSN: 15417786 NLM ISO Abbreviation: Mol Cancer Res Subsets: MEDLINE
أسماء مطبوعة: Original Publication: Philadelphia, PA : American Association for Cancer Research, c2002-
مواضيع طبية MeSH: Adenocarcinoma of Lung*/drug therapy , Adenocarcinoma of Lung*/genetics , Lung Neoplasms*/drug therapy , Lung Neoplasms*/genetics , Lung Neoplasms*/pathology, Autophagy ; Cell Line, Tumor ; Chelating Agents/pharmacology ; Chelating Agents/therapeutic use ; Copper/chemistry ; Copper/metabolism ; Copper/pharmacology ; Humans ; Protein Kinase Inhibitors/pharmacology ; Proto-Oncogene Proteins B-raf/metabolism
مستخلص: The transition metal copper (Cu) is an essential micronutrient required for development and proliferation, but the molecular mechanisms by which Cu contributes to these processes is not fully understood. Although traditionally studied as a static cofactor critical for the function of Cu-dependent enzymes, an expanding role for Cu is emerging to include its novel function as a dynamic mediator of signaling processes through the direct control of protein kinase activity. We now appreciate that Cu directly binds to and influences MEK1/2 and ULK1/2 kinase activity, and show here that reductions in MAPK and autophagic signaling are associated with dampened growth and survival of oncogenic BRAF-driven lung adenocarcinoma cells upon loss of Ctr1. Efficient autophagy, clonogenic survival, and tumorigenesis of BRAF-mutant cells required ULK1 Cu-binding. Although treatment with canonical MAPK inhibitors resulted in the upregulation of protective autophagy, mechanistically, the Cu chelator tetrathiomolybdate (TTM) was sufficient to target both autophagic and MAPK signaling as a means to blunt BRAF-driven tumorigenic properties. These findings support leveraging Cu chelation with TTM as an alternative therapeutic strategy to impair autophagy and MAPK signaling. As traditional MAPK monotherapies initiate autophagy signaling and promote cancer cell survival.
Implications: We establish that copper chelation therapy inhibits both autophagy and MAPK signaling in BRAFV600E-driven lung adenocarcinoma, thus overcoming the upregulation of protective autophagy elicited by canonical MAPK pathway inhibitors.
(©2022 The Authors; Published by the American Association for Cancer Research.)
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معلومات مُعتمدة: F31 CA243294 United States CA NCI NIH HHS; P30 ES013508 United States ES NIEHS NIH HHS; R35 GM124749 United States GM NIGMS NIH HHS
المشرفين على المادة: 0 (Chelating Agents)
0 (Protein Kinase Inhibitors)
789U1901C5 (Copper)
EC 2.7.11.1 (Proto-Oncogene Proteins B-raf)
تواريخ الأحداث: Date Created: 20220323 Date Completed: 20220708 Latest Revision: 20230106
رمز التحديث: 20231215
مُعرف محوري في PubMed: PMC9262833
DOI: 10.1158/1541-7786.MCR-21-0250
PMID: 35320362
قاعدة البيانات: MEDLINE
الوصف
تدمد:1557-3125
DOI:10.1158/1541-7786.MCR-21-0250