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 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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Author:Michael DiPrima, Dunrui Wang, Tröster, Alix TrösterGND, Dragan Maric, Nekane Terrades-Garcia, Taekyu Ha, Hyeongil Kwak, David Sánchez-Martín, Denis KudlinzkiGND, Harald SchwalbeORCiDGND, Giovanna Tosato
Pubmed Id:
Parent Title (English):Molecular oncology
Publisher:John Wiley & Sons, Inc.
Place of publication:Hoboken, NJ
Document Type:Article
Year of Completion:2019
Date of first Publication:2019/09/23
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2020/06/24
Tag:Eph receptors; Ephrin ligand; cell death; colorectal cancer; tyrosine kinase signaling
Page Number:19
First Page:2441
Last Page:2456
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Institutes:Biochemie, Chemie und Pharmazie / Biochemie und Chemie
Exzellenzcluster / Exzellenzcluster Makromolekulare Komplexe
Wissenschaftliche Zentren und koordinierte Programme / Sonderforschungsbereiche / Forschungskollegs
Wissenschaftliche Zentren und koordinierte Programme / Zentrum für Biomolekulare Magnetische Resonanz (BMRZ)
Dewey Decimal Classification:5 Naturwissenschaften und Mathematik / 57 Biowissenschaften; Biologie / 570 Biowissenschaften; Biologie
6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Licence (German):License LogoCreative Commons - Namensnennung 4.0