TY - JOUR
T1 - APE1 upregulates MMP-14 via redox-sensitive ARF6-mediated recycling to promote cell invasion of esophageal adenocarcinoma
AU - Lu, Heng
AU - Bhat, Ajaz A.
AU - Peng, Dunfa
AU - Chen, Zheng
AU - Zhu, Shoumin
AU - Hong, Jun
AU - Maacha, Selma
AU - Yan, Jin
AU - Robbins, David J.
AU - Kay Washington, M.
AU - Belkhiri, Abbes
AU - El-Rifai, Wael
N1 - Funding Information:
Research reported in this publication was supported by the U.S. National Cancer Institute of the National Institutes of Health under Award Numbers RO1CA224366, RO1CA206563, and P30CA240139. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health, University of Miami, or Department of Veterans Affairs.
Publisher Copyright:
© 2019 American Association for Cancer Research.
PY - 2019/9/1
Y1 - 2019/9/1
N2 - Esophageal adenocarcinoma (EAC) is an aggressive malignancy with poor clinical outcome. The incidence of EAC has been rising rapidly in the past three decades. Here, we showed that apurinic/apyrimidinic endonuclease (APE1) is overexpressed in EAC cell lines, and patients' samples of dysplasia and EAC. Downregulation of APE1 or inhibition of its redox function significantly repressed invasion. Overexpression of a redox-defective mutant, C65A, abrogated the proinvasive phenotype of APE1. APE1 regulated invasion via upregulation of matrix metalloproteinase 14 (MMP-14), which subsequently activated MMP-2, leading to degradation of the extracellular matrix in a redox-dependent manner. Downregulation of APE1 or inhibition of its redox function decreased the rate of endocytosis and recycling of MMP-14 protein. APE1 interacted with ARF6, a key regulator of MMP-14 recycling, which maintained ARF6 activity in an APE1-redox-dependent manner, promoting its ability to regulate MMP-14 recycling to the cell surface. In summary, these findings identify a novel redox-sensitive APE1-ARF6-MMP-14 signaling axis that mediates cellular invasion in esophageal carcinogenesis.
AB - Esophageal adenocarcinoma (EAC) is an aggressive malignancy with poor clinical outcome. The incidence of EAC has been rising rapidly in the past three decades. Here, we showed that apurinic/apyrimidinic endonuclease (APE1) is overexpressed in EAC cell lines, and patients' samples of dysplasia and EAC. Downregulation of APE1 or inhibition of its redox function significantly repressed invasion. Overexpression of a redox-defective mutant, C65A, abrogated the proinvasive phenotype of APE1. APE1 regulated invasion via upregulation of matrix metalloproteinase 14 (MMP-14), which subsequently activated MMP-2, leading to degradation of the extracellular matrix in a redox-dependent manner. Downregulation of APE1 or inhibition of its redox function decreased the rate of endocytosis and recycling of MMP-14 protein. APE1 interacted with ARF6, a key regulator of MMP-14 recycling, which maintained ARF6 activity in an APE1-redox-dependent manner, promoting its ability to regulate MMP-14 recycling to the cell surface. In summary, these findings identify a novel redox-sensitive APE1-ARF6-MMP-14 signaling axis that mediates cellular invasion in esophageal carcinogenesis.
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U2 - 10.1158/0008-5472.CAN-19-0237
DO - 10.1158/0008-5472.CAN-19-0237
M3 - Article
C2 - 31308045
AN - SCOPUS:85071787494
VL - 79
SP - 4426
EP - 4438
JO - Cancer Research
JF - Cancer Research
SN - 0008-5472
IS - 17
ER -