Unbiased Proteomic Profiling Uncovers a Targetable GNAS/PKA/PP2A Axis in Small Cell Lung Cancer Stem Cells.

A549 Cells Animals Antineoplastic Agents / administration & dosage Cell Line, Tumor Chromogranins / genetics Cisplatin / administration & dosage Cyclic AMP-Dependent Protein Kinases / genetics GTP-Binding Protein alpha Subunits, Gs / genetics Humans Lung Neoplasms / drug therapy Mice, Inbred NOD Mice, Knockout Mice, SCID Neoplastic Stem Cells / metabolism Protein Phosphatase 2 / genetics Proteomics / methods Signal Transduction / drug effects Small Cell Lung Carcinoma / drug therapy Xenograft Model Antitumor Assays / methods
GNAS PKA PP2A SCLC cancer cancer stem cells kinase lung neuroendocrine phosphatase proteomics

Journal

Cancer cell
ISSN: 1878-3686
Titre abrégé: Cancer Cell
Pays: United States
ID NLM: 101130617

Informations de publication

Date de publication:
13 07 2020
Historique:
received: 20 02 2019
revised: 18 02 2020
accepted: 04 05 2020
pubmed: 13 6 2020
medline: 9 3 2021
entrez: 13 6 2020
Statut: ppublish

Résumé

Using unbiased kinase profiling, we identified protein kinase A (PKA) as an active kinase in small cell lung cancer (SCLC). Inhibition of PKA activity genetically, or pharmacologically by activation of the PP2A phosphatase, suppresses SCLC expansion in culture and in vivo. Conversely, GNAS (G-protein α subunit), a PKA activator that is genetically activated in a small subset of human SCLC, promotes SCLC development. Phosphoproteomic analyses identified many PKA substrates and mechanisms of action. In particular, PKA activity is required for the propagation of SCLC stem cells in transplantation studies. Broad proteomic analysis of recalcitrant cancers has the potential to uncover targetable signaling networks, such as the GNAS/PKA/PP2A axis in SCLC.

Identifiants

DOI: 10.1016/j.ccell.2020.05.003 PMID: 32531271 PMC: PMC7363571
pubmed: 32531271
pii: S1535-6108(20)30253-1
doi: 10.1016/j.ccell.2020.05.003
pmc: PMC7363571
mid: NIHMS1594342
pii:
doi:

Substances chimiques

Antineoplastic Agents 0
Chromogranins 0
Cyclic AMP-Dependent Protein Kinases EC 2.7.11.11
Protein Phosphatase 2 EC 3.1.3.16
GNAS protein, human EC 3.6.1.-
GTP-Binding Protein alpha Subunits, Gs EC 3.6.5.1
Cisplatin Q20Q21Q62J

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S.

Langues

eng

Sous-ensembles de citation

IM

Pagination

129-143.e7

Subventions

Organisme : NCI NIH HHS
ID : T32 CA009302
Pays : United States
Organisme : NCI NIH HHS
ID : U54 CA217450
Pays : United States
Organisme : NCI NIH HHS
ID : U24 CA213274
Pays : United States
Organisme : NCI NIH HHS
ID : U01 CA231851
Pays : United States
Organisme : NIEHS NIH HHS
ID : R01 ES028096
Pays : United States
Organisme : Howard Hughes Medical Institute
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA244550
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA201513
Pays : United States
Organisme : NCI NIH HHS
ID : R35 CA231997
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM064337
Pays : United States
Organisme : NIA NIH HHS
ID : T32 AG047126
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA181654
Pays : United States
Organisme : NIH HHS
ID : S10 OD016229
Pays : United States
Organisme : NIBIB NIH HHS
ID : T32 EB009383
Pays : United States

Informations de copyright

Copyright © 2020 Elsevier Inc. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of Interests M.O. acknowledges Partnership for New York City for a BioAccelerate Award, funding large-scale synthesis of SMAP-1154. Mt. Sinai has filed patents on behalf of M.O. on SMAP-1154 and SMAP-DT-061. CWRU has filed a patent on behalf of M.O. and G.N. describing combinations of '1154 and '061 with kinase inhibitors. G.N. has an ownership interest in RAPPTA Therapeutics LLC. D.K.N. is a co-founder, shareholder, and scientific adviser for Artris Therapeutics and Frontier Medicines. J. Sage receives research funding from Stemcentrx/Abbvie, Pfizer, and Revolution Medicines and owns stock in Forty Seven Inc.

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Auteurs

Garry L Coles (GL)

Department of Pediatrics, Stanford University, 265 Campus Drive, Stanford, CA 94305-5457, USA; Department of Genetics, Stanford University, Stanford, CA 94305, USA.

Sandra Cristea (S)

Department of Pediatrics, Stanford University, 265 Campus Drive, Stanford, CA 94305-5457, USA; Department of Genetics, Stanford University, Stanford, CA 94305, USA.

James T Webber (JT)

Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA 94158, USA.

Rebecca S Levin (RS)

Howard Hughes Medical Institute, University of California San Francisco, San Francisco, CA 94158, USA; Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, CA 94158, USA.

Steven M Moss (SM)

Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, CA 94158, USA.

Andy He (A)

Department of Pediatrics, Stanford University, 265 Campus Drive, Stanford, CA 94305-5457, USA; Department of Genetics, Stanford University, Stanford, CA 94305, USA.

Jaya Sangodkar (J)

Division of Genetic Medicine, Michigan Medicine, University of Michigan, Ann Arbor, MI, USA.

Yeonjoo C Hwang (YC)

Department of Medicine, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA.

Julia Arand (J)

Department of Pediatrics, Stanford University, 265 Campus Drive, Stanford, CA 94305-5457, USA; Department of Genetics, Stanford University, Stanford, CA 94305, USA.

Alexandros P Drainas (AP)

Department of Pediatrics, Stanford University, 265 Campus Drive, Stanford, CA 94305-5457, USA; Department of Genetics, Stanford University, Stanford, CA 94305, USA.

Nancie A Mooney (NA)

Baxter Laboratory, Stanford University, Stanford, CA 94305, USA; Department of Microbiology & Immunology, Stanford University, Stanford, CA 94305, USA.

Janos Demeter (J)

Baxter Laboratory, Stanford University, Stanford, CA 94305, USA; Department of Microbiology & Immunology, Stanford University, Stanford, CA 94305, USA.

Jessica N Spradlin (JN)

Department of Chemistry, University of California, Berkeley, Berkeley, CA 94720, USA.

Brandon Mauch (B)

Department of Pediatrics, Stanford University, 265 Campus Drive, Stanford, CA 94305-5457, USA; Department of Genetics, Stanford University, Stanford, CA 94305, USA.

Vicky Le (V)

Department of Pediatrics, Stanford University, 265 Campus Drive, Stanford, CA 94305-5457, USA; Department of Genetics, Stanford University, Stanford, CA 94305, USA.

Yan Ting Shue (YT)

Department of Pediatrics, Stanford University, 265 Campus Drive, Stanford, CA 94305-5457, USA; Department of Genetics, Stanford University, Stanford, CA 94305, USA.

Julie H Ko (JH)

Department of Pediatrics, Stanford University, 265 Campus Drive, Stanford, CA 94305-5457, USA; Department of Genetics, Stanford University, Stanford, CA 94305, USA.

Myung Chang Lee (MC)

Department of Pediatrics, Stanford University, 265 Campus Drive, Stanford, CA 94305-5457, USA; Department of Genetics, Stanford University, Stanford, CA 94305, USA.

Christina Kong (C)

Department of Pathology, Stanford University, Stanford, CA 94305, USA.

Daniel K Nomura (DK)

Department of Chemistry, University of California, Berkeley, Berkeley, CA 94720, USA; Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA; Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA.

Michael Ohlmeyer (M)

Icahn School of Medicine at Mount Sinai, New York, NY, USA; Atux Iskay LLC, Plainsboro, New Jersey, NJ 08536, USA.

Danielle L Swaney (DL)

Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, CA 94158, USA; Quantitative Biosciences Institute (QBI), University of California San Francisco, San Francisco, CA 94158, USA; David J. Gladstone Institute, University of California San Francisco, San Francisco, CA 94158, USA.

Nevan J Krogan (NJ)

Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, CA 94158, USA; Quantitative Biosciences Institute (QBI), University of California San Francisco, San Francisco, CA 94158, USA; David J. Gladstone Institute, University of California San Francisco, San Francisco, CA 94158, USA.

Peter K Jackson (PK)

Baxter Laboratory, Stanford University, Stanford, CA 94305, USA; Department of Microbiology & Immunology, Stanford University, Stanford, CA 94305, USA; Department of Pathology, Stanford University, Stanford, CA 94305, USA.

Goutham Narla (G)

Division of Genetic Medicine, Michigan Medicine, University of Michigan, Ann Arbor, MI, USA.

John D Gordan (JD)

Department of Medicine, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA; Quantitative Biosciences Institute (QBI), University of California San Francisco, San Francisco, CA 94158, USA.

Kevan M Shokat (KM)

Howard Hughes Medical Institute, University of California San Francisco, San Francisco, CA 94158, USA; Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, CA 94158, USA.

Julien Sage (J)

Department of Pediatrics, Stanford University, 265 Campus Drive, Stanford, CA 94305-5457, USA; Department of Genetics, Stanford University, Stanford, CA 94305, USA. Electronic address: julsage@stanford.edu.

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Classifications MeSH

questionsmedicales.fr › Cellules › Cellules épithéliales › Cellules A549 › Unbiased Proteomic Profiling Uncovers a...
questionsmedicales.fr › Eucaryotes › Animaux › Unbiased Proteomic Profiling Uncovers a...
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Utilisations thérapeutiques › Antinéoplasiques › Unbiased Proteomic Profiling Uncovers a...
questionsmedicales.fr › Cellules › Cellules cultivées › Cellules cancéreuses en culture › Lignée cellulaire tumorale › Unbiased Proteomic Profiling Uncovers a...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Précurseurs de protéines › Chromogranine › Unbiased Proteomic Profiling Uncovers a...
questionsmedicales.fr › Produits chimiques inorganiques › Composés du platine › Cisplatine › Unbiased Proteomic Profiling Uncovers a...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Protein-Serine-Threonine Kinases › Cyclic Nucleotide-Regulated Protein Kinases › Cyclic AMP-Dependent Protein Kinases › Unbiased Proteomic Profiling Uncovers a...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines membranaires › Protéines G hétérotrimériques › Sous-unités alpha des protéines G › Sous-unités alpha Gs des protéines G › Unbiased Proteomic Profiling Uncovers a...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Unbiased Proteomic Profiling Uncovers a...
questionsmedicales.fr › Maladies de l'appareil respiratoire › Tumeurs de l'appareil respiratoire › Tumeurs du poumon › Unbiased Proteomic Profiling Uncovers a...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Lignées consanguines de souris › Souris de lignée NOD › Unbiased Proteomic Profiling Uncovers a...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Souris transgéniques › Souris knockout › Unbiased Proteomic Profiling Uncovers a...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Souches mutantes de souris › Souris SCID › Unbiased Proteomic Profiling Uncovers a...
questionsmedicales.fr › Cellules › Cellules souches › Cellules souches tumorales › Unbiased Proteomic Profiling Uncovers a...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Phosphoprotein Phosphatases › Protein Phosphatase 2 › Unbiased Proteomic Profiling Uncovers a...
questionsmedicales.fr › Disciplines des sciences naturelles › Chimie › Biochimie › Protéomique › Unbiased Proteomic Profiling Uncovers a...
questionsmedicales.fr › Phénomènes physiologiques cellulaires › Transduction du signal › Unbiased Proteomic Profiling Uncovers a...
questionsmedicales.fr › Maladies de l'appareil respiratoire › Tumeurs de l'appareil respiratoire › Tumeurs du poumon › Tumeurs des bronches › Carcinome bronchogénique › Carcinome pulmonaire à petites cellules › Unbiased Proteomic Profiling Uncovers a...
questionsmedicales.fr › Techniques d'investigation › Transplantation tumorale › Tests d'activité antitumorale sur modèle de xénogreffe › Unbiased Proteomic Profiling Uncovers a...