Abstract
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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenocarcinoma / genetics
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Adenocarcinoma / metabolism
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Adenocarcinoma / pathology*
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Animals
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Axl Receptor Tyrosine Kinase
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Benzocycloheptenes / pharmacology
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Biological Transport
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Cathepsin B / genetics
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Cathepsin B / metabolism
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Cell Line, Tumor
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Chick Embryo
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Chorioallantoic Membrane / metabolism
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Epithelial-Mesenchymal Transition / genetics
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Esophageal Neoplasms / genetics
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Esophageal Neoplasms / metabolism
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Esophageal Neoplasms / pathology*
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Gene Expression Regulation, Neoplastic
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Humans
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Hydrogen-Ion Concentration
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Lactates / metabolism
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Lysosomes / chemistry
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Lysosomes / metabolism*
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Lysosomes / pathology
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Monocarboxylic Acid Transporters / genetics
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Monocarboxylic Acid Transporters / metabolism
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Proto-Oncogene Proteins / antagonists & inhibitors
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism*
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Receptor Protein-Tyrosine Kinases / antagonists & inhibitors
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Receptor Protein-Tyrosine Kinases / genetics
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Receptor Protein-Tyrosine Kinases / metabolism*
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Symporters / genetics
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Symporters / metabolism
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Triazoles / pharmacology
Substances
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Benzocycloheptenes
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Lactates
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Monocarboxylic Acid Transporters
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Proto-Oncogene Proteins
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Symporters
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Triazoles
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monocarboxylate transport protein 1
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bemcentinib
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Receptor Protein-Tyrosine Kinases
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CTSB protein, human
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Cathepsin B
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Axl Receptor Tyrosine Kinase
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AXL protein, human
Supplementary concepts
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Adenocarcinoma Of Esophagus