Open AccessIdentification of Eph receptor signaling as a regulator of autophagy and a therapeutic target in colorectal carcinoma
Author(s) -
DiPrima Michael,
Wang Dunrui,
Tröster Alix,
Maric Dragan,
TerradesGarcia Nekane,
Ha Taekyu,
Kwak Hyeongil,
SanchezMartin David,
Kudlinzki Denis,
Schwalbe Harald,
Tosato Giovanna
Publication year - 2019
Publication title -
molecular oncology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.332
H-Index - 88
eISSN - 1878-0261
pISSN - 1574-7891
DOI - 10.1002/1878-0261.12576
Subject(s) - erythropoietin producing hepatocellular (eph) receptor , ephrin , cancer research , colorectal cancer , autophagy , tyrosine kinase , biology , receptor tyrosine kinase , signal transduction , cancer , medicine , microbiology and biotechnology , apoptosis , biochemistry
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.