Identification of Eph receptor signaling as a regulator of autophagy and a therapeutic target in colorectal carcinoma
Identifieur interne : 000A42 ( Ncbi/Checkpoint ); précédent : 000A41; suivant : 000A43Identification 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
Url:
DOI: 10.1002/1878-0261.12576
PubMed: 31545551
PubMed Central: 6822245
Affiliations:
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D" first="Dunrui" last="Wang">Dunrui Wang</name><affiliation><nlm:aff id="mol212576-aff-0001"></nlm:aff></affiliation></author><author><name sortKey="Troster, Alix" sort="Troster, Alix" uniqKey="Troster A" first="Alix" last="Tröster">Alix Tröster</name><affiliation><nlm:aff 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 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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><affiliations><list></list><tree><noCountry><name sortKey="Diprima, Michael" sort="Diprima, Michael" uniqKey="Diprima M" first="Michael" last="Diprima">Michael Diprima</name><name sortKey="Ha, Taekyu" sort="Ha, Taekyu" uniqKey="Ha T" first="Taekyu" last="Ha">Taekyu Ha</name><name sortKey="Kudlinzki, Denis" sort="Kudlinzki, Denis" uniqKey="Kudlinzki D" first="Denis" last="Kudlinzki">Denis Kudlinzki</name><name sortKey="Kwak, Hyeongil" sort="Kwak, Hyeongil" uniqKey="Kwak H" first="Hyeongil" last="Kwak">Hyeongil Kwak</name><name sortKey="Maric, Dragan" sort="Maric, Dragan" uniqKey="Maric D" first="Dragan" last="Maric">Dragan Maric</name><name sortKey="Sanchez Artin, David" sort="Sanchez Artin, David" uniqKey="Sanchez Artin D" first="David" last="Sanchez-Martin">David Sanchez-Martin</name><name sortKey="Schwalbe, Harald" sort="Schwalbe, Harald" uniqKey="Schwalbe H" first="Harald" last="Schwalbe">Harald Schwalbe</name><name sortKey="Terrades Arcia, Nekane" sort="Terrades Arcia, Nekane" uniqKey="Terrades Arcia N" first="Nekane" last="Terrades-Garcia">Nekane Terrades-Garcia</name><name sortKey="Tosato, Giovanna" sort="Tosato, Giovanna" uniqKey="Tosato G" first="Giovanna" last="Tosato">Giovanna Tosato</name><name sortKey="Troster, Alix" sort="Troster, Alix" uniqKey="Troster A" first="Alix" last="Tröster">Alix Tröster</name><name sortKey="Wang, Dunrui" sort="Wang, Dunrui" uniqKey="Wang D" first="Dunrui" last="Wang">Dunrui Wang</name></noCountry></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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