Abstract
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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 4426-4438 |
| Number of pages | 13 |
| Journal | Cancer Research |
| Volume | 79 |
| Issue number | 17 |
| DOIs | |
| State | Published - Sep 1 2019 |
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ASJC Scopus subject areas
- Oncology
- Cancer Research
Cite this
APE1 upregulates MMP-14 via redox-sensitive ARF6-mediated recycling to promote cell invasion of esophageal adenocarcinoma. / Lu, Heng; Bhat, Ajaz A.; Peng, Dunfa; Chen, Zheng; Zhu, Shoumin; Hong, Jun; Maacha, Selma; Yan, Jin; Robbins, David J.; Kay Washington, M.; Belkhiri, Abbes; El-Rifai, Wael.
In: Cancer Research, Vol. 79, No. 17, 01.09.2019, p. 4426-4438.Research output: Contribution to journal › Article
}
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
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.
UR - http://www.scopus.com/inward/record.url?scp=85071787494&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85071787494&partnerID=8YFLogxK
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 - Journal of Cancer Research
JF - Journal of Cancer Research
SN - 0099-7013
IS - 17
ER -