APE1 upregulates MMP-14 via redox-sensitive ARF6-mediated recycling to promote cell invasion of esophageal adenocarcinoma

Heng Lu, Ajaz A. Bhat, Dunfa Peng, Zheng Chen, Shoumin Zhu, Jun Hong, Selma Maacha, Jin Yan, David J. Robbins, M. Kay Washington, Abbes Belkhiri, Wael El-Rifai

Research output: Contribution to journalArticle

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 languageEnglish (US)
Pages (from-to)4426-4438
Number of pages13
JournalCancer Research
Volume79
Issue number17
DOIs
StatePublished - Sep 1 2019

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Matrix Metalloproteinase 14
Recycling
Oxidation-Reduction
Adenocarcinoma
Up-Regulation
Down-Regulation
DNA-(Apurinic or Apyrimidinic Site) Lyase
Endocytosis
Matrix Metalloproteinases
Extracellular Matrix
Carcinogenesis
Phenotype
Cell Line
Incidence
Neoplasms

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 journalArticle

Lu, H, Bhat, AA, Peng, D, Chen, Z, Zhu, S, Hong, J, Maacha, S, Yan, J, Robbins, DJ, Kay Washington, M, Belkhiri, A & El-Rifai, W 2019, 'APE1 upregulates MMP-14 via redox-sensitive ARF6-mediated recycling to promote cell invasion of esophageal adenocarcinoma', Cancer Research, vol. 79, no. 17, pp. 4426-4438. https://doi.org/10.1158/0008-5472.CAN-19-0237
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. / APE1 upregulates MMP-14 via redox-sensitive ARF6-mediated recycling to promote cell invasion of esophageal adenocarcinoma. In: Cancer Research. 2019 ; Vol. 79, No. 17. pp. 4426-4438.
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AU - Zhu, Shoumin

AU - Hong, Jun

AU - Maacha, Selma

AU - Yan, Jin

AU - Robbins, David J.

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AU - El-Rifai, Wael

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