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Identification of Eph receptor signaling as a regulator of autophagy and a therapeutic target in colorectal carcinoma

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 a...

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Autores principales: DiPrima, Michael, Wang, Dunrui, Tröster, Alix, Maric, Dragan, Terrades‐Garcia, Nekane, Ha, Taekyu, Kwak, Hyeongil, Sanchez‐Martin, David, Kudlinzki, Denis, Schwalbe, Harald, Tosato, Giovanna
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6822245/
https://www.ncbi.nlm.nih.gov/pubmed/31545551
http://dx.doi.org/10.1002/1878-0261.12576
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author DiPrima, Michael
Wang, Dunrui
Tröster, Alix
Maric, Dragan
Terrades‐Garcia, Nekane
Ha, Taekyu
Kwak, Hyeongil
Sanchez‐Martin, David
Kudlinzki, Denis
Schwalbe, Harald
Tosato, Giovanna
author_facet DiPrima, Michael
Wang, Dunrui
Tröster, Alix
Maric, Dragan
Terrades‐Garcia, Nekane
Ha, Taekyu
Kwak, Hyeongil
Sanchez‐Martin, David
Kudlinzki, Denis
Schwalbe, Harald
Tosato, Giovanna
author_sort DiPrima, Michael
collection PubMed
description 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 in vitro 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.
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spelling pubmed-68222452019-11-06 Identification of Eph receptor signaling as a regulator of autophagy and a therapeutic target in colorectal carcinoma DiPrima, Michael Wang, Dunrui Tröster, Alix Maric, Dragan Terrades‐Garcia, Nekane Ha, Taekyu Kwak, Hyeongil Sanchez‐Martin, David Kudlinzki, Denis Schwalbe, Harald Tosato, Giovanna Mol Oncol Research Articles 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 in vitro 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. John Wiley and Sons Inc. 2019-10-23 2019-11 /pmc/articles/PMC6822245/ /pubmed/31545551 http://dx.doi.org/10.1002/1878-0261.12576 Text en © 2019 The Authors. Published by FEBS Press and John Wiley & Sons Ltd. This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Articles
DiPrima, Michael
Wang, Dunrui
Tröster, Alix
Maric, Dragan
Terrades‐Garcia, Nekane
Ha, Taekyu
Kwak, Hyeongil
Sanchez‐Martin, David
Kudlinzki, Denis
Schwalbe, Harald
Tosato, Giovanna
Identification of Eph receptor signaling as a regulator of autophagy and a therapeutic target in colorectal carcinoma
title Identification of Eph receptor signaling as a regulator of autophagy and a therapeutic target in colorectal carcinoma
title_full Identification of Eph receptor signaling as a regulator of autophagy and a therapeutic target in colorectal carcinoma
title_fullStr Identification of Eph receptor signaling as a regulator of autophagy and a therapeutic target in colorectal carcinoma
title_full_unstemmed Identification of Eph receptor signaling as a regulator of autophagy and a therapeutic target in colorectal carcinoma
title_short Identification of Eph receptor signaling as a regulator of autophagy and a therapeutic target in colorectal carcinoma
title_sort identification of eph receptor signaling as a regulator of autophagy and a therapeutic target in colorectal carcinoma
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6822245/
https://www.ncbi.nlm.nih.gov/pubmed/31545551
http://dx.doi.org/10.1002/1878-0261.12576
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