AXL Mediates Esophageal Adenocarcinoma Cell Invasion through Regulation of Extracellular Acidification and Lysosome Trafficking.

Maacha S, Hong J, von Lersner A, Zijlstra A, Belkhiri A
Neoplasia. 2018 20 (10): 1008-1022

PMID: 30189359 · PMCID: PMC6126204 · DOI:10.1016/j.neo.2018.08.005

Esophageal adenocarcinoma (EAC) is a highly aggressive malignancy that is characterized by resistance to chemotherapy and a poor clinical outcome. The overexpression of the receptor tyrosine kinase AXL is frequently associated with unfavorable prognosis in EAC. Although it is well documented that AXL mediates cancer cell invasion as a downstream effector of epithelial-to-mesenchymal transition, the precise molecular mechanism underlying this process is not completely understood. Herein, we demonstrate for the first time that AXL mediates cell invasion through the regulation of lysosomes peripheral distribution and cathepsin B secretion in EAC cell lines. Furthermore, we show that AXL-dependent peripheral distribution of lysosomes and cell invasion are mediated by extracellular acidification, which is potentiated by AXL-induced secretion of lactate through AKT-NF-κB-dependent MCT-1 regulation. Our novel mechanistic findings support future clinical studies to evaluate the therapeutic potential of the AXL inhibitor R428 (BGB324) in highly invasive EAC.

Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

MeSH Terms (20)

Adenocarcinoma Animals Benzocycloheptenes Biological Transport Cathepsin B Cell Line, Tumor Chick Embryo Chorioallantoic Membrane Epithelial-Mesenchymal Transition Esophageal Neoplasms Gene Expression Regulation, Neoplastic Humans Hydrogen-Ion Concentration Lactates Lysosomes Monocarboxylic Acid Transporters Proto-Oncogene Proteins Receptor Protein-Tyrosine Kinases Symporters Triazoles

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