Identification of Eph receptor signaling as a regulator of autophagy and a therapeutic target in colorectal carcinoma
Identifieur interne : 000707 ( Pmc/Curation ); précédent : 000706; suivant : 000708Identification of Eph receptor signaling as a regulator of autophagy and a therapeutic target in colorectal carcinoma
Auteurs : Michael Diprima ; Dunrui Wang ; Alix Tröster ; Dragan Maric ; Nekane Terrades-Garcia ; Taekyu Ha ; Hyeongil Kwak ; David Sanchez-Martin ; Denis Kudlinzki ; Harald Schwalbe ; Giovanna TosatoSource :
- Molecular Oncology [ 1574-7891 ] ; 2019.
Abstract
Advanced colorectal carcinoma is currently incurable, and new therapies are urgently needed. We report that phosphotyrosine‐dependent Eph receptor signaling sustains colorectal carcinoma cell survival, thereby uncovering a survival pathway active in colorectal carcinoma cells. We find that genetic and biochemical inhibition of Eph tyrosine kinase activity or depletion of the Eph ligand EphrinB2 reproducibly induces colorectal carcinoma cell death by autophagy. Spautin and 3‐methyladenine, inhibitors of early steps in the autophagic pathway, significantly reduce autophagy‐mediated cell death that follows inhibition of phosphotyrosine‐dependent Eph signaling in colorectal cancer cells. A small‐molecule inhibitor of the Eph kinase, NVP‐BHG712 or its regioisomer NVP‐Iso, reduces human colorectal cancer cell growth
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DOI: 10.1002/1878-0261.12576
PubMed: 31545551
PubMed Central: 6822245
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id="mol212576-aff-0002"></nlm:aff></affiliation></author><author><name sortKey="Maric, Dragan" sort="Maric, Dragan" uniqKey="Maric D" first="Dragan" last="Maric">Dragan Maric</name><affiliation><nlm:aff id="mol212576-aff-0003"></nlm:aff></affiliation></author><author><name sortKey="Terrades Arcia, Nekane" sort="Terrades Arcia, Nekane" uniqKey="Terrades Arcia N" first="Nekane" last="Terrades-Garcia">Nekane Terrades-Garcia</name><affiliation><nlm:aff id="mol212576-aff-0004"></nlm:aff></affiliation></author><author><name sortKey="Ha, Taekyu" sort="Ha, Taekyu" uniqKey="Ha T" first="Taekyu" last="Ha">Taekyu Ha</name><affiliation><nlm:aff id="mol212576-aff-0001"></nlm:aff></affiliation></author><author><name sortKey="Kwak, Hyeongil" sort="Kwak, Hyeongil" uniqKey="Kwak H" first="Hyeongil" last="Kwak">Hyeongil Kwak</name><affiliation><nlm:aff id="mol212576-aff-0001"></nlm:aff></affiliation></author><author><name sortKey="Sanchez Artin, David" sort="Sanchez Artin, David" uniqKey="Sanchez Artin D" first="David" last="Sanchez-Martin">David Sanchez-Martin</name><affiliation><nlm:aff id="mol212576-aff-0001"></nlm:aff></affiliation></author><author><name sortKey="Kudlinzki, Denis" sort="Kudlinzki, Denis" uniqKey="Kudlinzki D" first="Denis" last="Kudlinzki">Denis Kudlinzki</name><affiliation><nlm:aff id="mol212576-aff-0002"></nlm:aff></affiliation></author><author><name sortKey="Schwalbe, Harald" sort="Schwalbe, Harald" uniqKey="Schwalbe H" first="Harald" last="Schwalbe">Harald Schwalbe</name><affiliation><nlm:aff id="mol212576-aff-0002"></nlm:aff></affiliation></author><author><name sortKey="Tosato, Giovanna" sort="Tosato, Giovanna" uniqKey="Tosato G" first="Giovanna" last="Tosato">Giovanna Tosato</name><affiliation><nlm:aff id="mol212576-aff-0001"></nlm:aff></affiliation></author></analytic><series><title level="j">Molecular Oncology</title><idno type="ISSN">1574-7891</idno><idno type="eISSN">1878-0261</idno><imprint><date when="2019">2019</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Advanced colorectal carcinoma is currently incurable, and new therapies are urgently needed. We report that phosphotyrosine‐dependent Eph receptor signaling sustains colorectal carcinoma cell survival, thereby uncovering a survival pathway active in colorectal carcinoma cells. We find that genetic and biochemical inhibition of Eph tyrosine kinase activity or depletion of the Eph ligand EphrinB2 reproducibly induces colorectal carcinoma cell death by autophagy. Spautin and 3‐methyladenine, inhibitors of early steps in the autophagic pathway, significantly reduce autophagy‐mediated cell death that follows inhibition of phosphotyrosine‐dependent Eph signaling in colorectal cancer cells. A small‐molecule inhibitor of the Eph kinase, NVP‐BHG712 or its regioisomer NVP‐Iso, reduces human colorectal cancer cell growth <italic>in vitro</italic> and tumor growth in mice. Colorectal cancers express the EphrinB ligand and its Eph receptors at significantly higher levels than numerous other cancer types, supporting Eph signaling inhibition as a potential new strategy for the broad treatment of colorectal carcinoma.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct></listBibl></div1></back></TEI><pmc article-type="research-article"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Mol Oncol</journal-id><journal-id journal-id-type="iso-abbrev">Mol Oncol</journal-id><journal-id journal-id-type="doi">10.1002/(ISSN)1878-0261</journal-id><journal-id journal-id-type="publisher-id">MOL2</journal-id><journal-title-group><journal-title>Molecular Oncology</journal-title></journal-title-group><issn pub-type="ppub">1574-7891</issn><issn pub-type="epub">1878-0261</issn><publisher><publisher-name>John Wiley and Sons Inc.</publisher-name><publisher-loc>Hoboken</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">31545551</article-id><article-id pub-id-type="pmc">6822245</article-id><article-id pub-id-type="doi">10.1002/1878-0261.12576</article-id><article-id pub-id-type="publisher-id">MOL212576</article-id><article-categories><subj-group subj-group-type="overline"><subject>Research Article</subject></subj-group><subj-group subj-group-type="heading"><subject>Research Articles</subject></subj-group></article-categories><title-group><article-title>Identification of Eph receptor signaling as a regulator of autophagy and a therapeutic target in colorectal carcinoma</article-title><alt-title alt-title-type="right-running-head">Targeting Eph receptors in colorectal cancer</alt-title><alt-title alt-title-type="left-running-head">M. DiPrima <italic>et al</italic>.</alt-title></title-group><contrib-group><contrib id="mol212576-cr-0001" contrib-type="author"><name><surname>DiPrima</surname><given-names>Michael</given-names></name><xref ref-type="aff" rid="mol212576-aff-0001"><sup>1</sup></xref></contrib><contrib id="mol212576-cr-0002" contrib-type="author"><name><surname>Wang</surname><given-names>Dunrui</given-names></name><xref ref-type="aff" rid="mol212576-aff-0001"><sup>1</sup></xref></contrib><contrib id="mol212576-cr-0003" contrib-type="author"><name><surname>Tröster</surname><given-names>Alix</given-names></name><xref ref-type="aff" rid="mol212576-aff-0002"><sup>2</sup></xref></contrib><contrib id="mol212576-cr-0004" contrib-type="author"><name><surname>Maric</surname><given-names>Dragan</given-names></name><xref ref-type="aff" rid="mol212576-aff-0003"><sup>3</sup></xref></contrib><contrib id="mol212576-cr-0005" contrib-type="author"><name><surname>Terrades‐Garcia</surname><given-names>Nekane</given-names></name><xref ref-type="aff" rid="mol212576-aff-0004"><sup>4</sup></xref></contrib><contrib id="mol212576-cr-0006" contrib-type="author"><name><surname>Ha</surname><given-names>Taekyu</given-names></name><xref ref-type="aff" rid="mol212576-aff-0001"><sup>1</sup></xref></contrib><contrib id="mol212576-cr-0007" contrib-type="author"><name><surname>Kwak</surname><given-names>Hyeongil</given-names></name><xref ref-type="aff" rid="mol212576-aff-0001"><sup>1</sup></xref></contrib><contrib id="mol212576-cr-0008" contrib-type="author"><name><surname>Sanchez‐Martin</surname><given-names>David</given-names></name><contrib-id contrib-id-type="orcid">https://orcid.org/0000-0002-2712-4762</contrib-id><xref ref-type="aff" rid="mol212576-aff-0001"><sup>1</sup></xref></contrib><contrib id="mol212576-cr-0009" contrib-type="author"><name><surname>Kudlinzki</surname><given-names>Denis</given-names></name><xref ref-type="aff" rid="mol212576-aff-0002"><sup>2</sup></xref></contrib><contrib id="mol212576-cr-0010" contrib-type="author"><name><surname>Schwalbe</surname><given-names>Harald</given-names></name><xref ref-type="aff" rid="mol212576-aff-0002"><sup>2</sup></xref></contrib><contrib id="mol212576-cr-0011" contrib-type="author" corresp="yes"><name><surname>Tosato</surname><given-names>Giovanna</given-names></name><contrib-id contrib-id-type="orcid">https://orcid.org/0000-0003-1663-3227</contrib-id><xref ref-type="aff" rid="mol212576-aff-0001"><sup>1</sup></xref><address><email>Tosatog@mail.nih.gov</email></address></contrib></contrib-group><aff id="mol212576-aff-0001"><label><sup>1</sup></label><named-content content-type="organisation-division">Laboratory of Cellular Oncology</named-content><named-content content-type="organisation-division">Center for Cancer Research (CCR)</named-content><institution>National Cancer Institute (NCI)</institution><named-content content-type="city">Bethesda</named-content><named-content content-type="country-part">MD</named-content><country country="US">USA</country></aff><aff id="mol212576-aff-0002"><label><sup>2</sup></label><named-content content-type="organisation-division">Center for Biomolecular Magnetic Resonance</named-content><named-content content-type="organisation-division">Institute for Organic Chemistry and Chemical Biology</named-content><institution>Johann Wolfgang Goethe‐University</institution><named-content content-type="city">Frankfurt am Main</named-content><country country="DE">Germany</country></aff><aff id="mol212576-aff-0003"><label><sup>3</sup></label><named-content content-type="organisation-division">National Institutes of Neurological Disorders and Stroke</named-content><institution>National Institutes of Health (NIH)</institution><named-content content-type="city">Bethesda</named-content><named-content content-type="country-part">MD</named-content><country country="US">USA</country></aff><aff id="mol212576-aff-0004"><label><sup>4</sup></label><named-content content-type="organisation-division">Vasculitis Research Unit</named-content><named-content content-type="organisation-division">Department of Autoimmune Diseases</named-content><named-content content-type="organisation-division">Hospital Clinic</named-content><institution>University of Barcelona</institution><country country="ES">Spain</country></aff><author-notes><corresp id="correspondenceTo"><label>*</label><bold>Correspondence</bold><break></break>G. Tosato, Laboratory of Cellular Oncology, Center for Cancer Research (CCR), National Cancer Institute (NCI), 37 Convent Drive, NIH Bethesda Campus, Building 37, Room 4124, Bethesda, MD 20892, USA<break></break>Tel: +1 240 760 6144<break></break>E‐mail: <email>Tosatog@mail.nih.gov</email><break></break></corresp></author-notes><pub-date pub-type="epub"><day>23</day><month>10</month><year>2019</year></pub-date><pub-date pub-type="ppub"><month>11</month><year>2019</year></pub-date><volume>13</volume><issue>11</issue><issue-id pub-id-type="doi">10.1002/mol2.v13.11</issue-id><fpage>2441</fpage><lpage>2459</lpage><history><date date-type="received"><day>05</day><month>4</month><year>2019</year></date><date date-type="rev-recd"><day>02</day><month>8</month><year>2019</year></date><date date-type="accepted"><day>20</day><month>9</month><year>2019</year></date></history><permissions><pmc-comment> © 2019 Federation of European Biochemical Societies </pmc-comment>
<copyright-statement content-type="article-copyright">© 2019 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.</copyright-statement><license license-type="creativeCommonsBy"><license-p>This is an open access article under the terms of the <ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">http://creativecommons.org/licenses/by/4.0/</ext-link> License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.</license-p></license></permissions><self-uri content-type="pdf" xlink:type="simple" xlink:href="file:MOL2-13-2441.pdf"></self-uri><abstract id="mol212576-abs-0001"><p>Advanced colorectal carcinoma is currently incurable, and new therapies are urgently needed. We report that phosphotyrosine‐dependent Eph receptor signaling sustains colorectal carcinoma cell survival, thereby uncovering a survival pathway active in colorectal carcinoma cells. We find that genetic and biochemical inhibition of Eph tyrosine kinase activity or depletion of the Eph ligand EphrinB2 reproducibly induces colorectal carcinoma cell death by autophagy. Spautin and 3‐methyladenine, inhibitors of early steps in the autophagic pathway, significantly reduce autophagy‐mediated cell death that follows inhibition of phosphotyrosine‐dependent Eph signaling in colorectal cancer cells. A small‐molecule inhibitor of the Eph kinase, NVP‐BHG712 or its regioisomer NVP‐Iso, reduces human colorectal cancer cell growth <italic>in vitro</italic> and tumor growth in mice. Colorectal cancers express the EphrinB ligand and its Eph receptors at significantly higher levels than numerous other cancer types, supporting Eph signaling inhibition as a potential new strategy for the broad treatment of colorectal carcinoma.</p></abstract><kwd-group kwd-group-type="author-generated"><kwd id="mol212576-kwd-0001">cell death</kwd><kwd id="mol212576-kwd-0002">colorectal cancer</kwd><kwd id="mol212576-kwd-0003">Eph receptors</kwd><kwd id="mol212576-kwd-0004">Ephrin ligand</kwd><kwd id="mol212576-kwd-0005">tyrosine kinase signaling</kwd></kwd-group><funding-group><award-group><funding-source>CCR/NCI/NIH</funding-source></award-group></funding-group><counts><fig-count count="7"></fig-count><table-count count="0"></table-count><page-count count="19"></page-count><word-count count="10411"></word-count></counts><custom-meta-group><custom-meta><meta-name>source-schema-version-number</meta-name><meta-value>2.0</meta-value></custom-meta><custom-meta><meta-name>component-id</meta-name><meta-value>mol212576</meta-value></custom-meta><custom-meta><meta-name>cover-date</meta-name><meta-value>November 2019</meta-value></custom-meta><custom-meta><meta-name>details-of-publishers-convertor</meta-name><meta-value>Converter:WILEY_ML3GV2_TO_NLMPMC version:5.7.0 mode:remove_FC converted:31.10.2019</meta-value></custom-meta></custom-meta-group></article-meta></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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