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Identification of Eph receptor signaling as a regulator of autophagy and a therapeutic target in colorectal carcinoma.
- Source :
-
Molecular oncology [Mol Oncol] 2019 Nov; Vol. 13 (11), pp. 2441-2459. Date of Electronic Publication: 2019 Oct 23. - Publication Year :
- 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 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.<br /> (© 2019 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.)
- Subjects :
- Animals
Cell Line, Tumor
Cell Proliferation drug effects
Cell Survival drug effects
Ephrin-B2 metabolism
Female
Gene Silencing drug effects
Mice
Mice, Nude
Protein Kinase Inhibitors pharmacology
Pyrazoles pharmacology
Pyrimidines pharmacology
Survival Analysis
Autophagy drug effects
Colorectal Neoplasms drug therapy
Colorectal Neoplasms pathology
Molecular Targeted Therapy
Receptors, Eph Family metabolism
Signal Transduction drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 1878-0261
- Volume :
- 13
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- Molecular oncology
- Publication Type :
- Academic Journal
- Accession number :
- 31545551
- Full Text :
- https://doi.org/10.1002/1878-0261.12576