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Asparaginyl endopeptidase improves the resistance of microtubule-targeting drugs in gastric cancer through IQGAP1 modulating the EGFR/JNK/ERK signaling pathway

Authors Cui Y, Li Q, Li H, Wang Y, Wang H, Chen W, Zhang S, Cao J, Liu T

Received 24 October 2016

Accepted for publication 27 December 2016

Published 3 February 2017 Volume 2017:10 Pages 627—643

DOI https://doi.org/10.2147/OTT.S125579

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Akshita Wason

Peer reviewer comments 2

Editor who approved publication: Dr Chiung-Kuei Huang

Yuehong Cui,1,* Qian Li,1,* Hong Li,1 Yan Wang,1 Hongshan Wang,2 Weidong Chen,2 Shangmin Zhang,3 Jian Cao,3 Tianshu Liu1

1Medical Oncology Department, 2General Surgery Department, Zhongshan Hospital, Fudan University, Shanghai, People’s Republic of China; 3Pathology Department, Yale School of Medicine, New Haven, CT, USA

*These authors contributed equally to this work

Purpose: In recent years, understanding of the role of asparaginyl endopeptidase (AEP) in tumorigenesis has steadily increased. In this study, we investigated whether AEP expression correlates with sensitivity to chemotherapeutic drugs in gastric cancer and explored the mechanism.
Patients and methods: AEP expression in the serum of patients’ peripheral blood was measured by enzyme-linked immunosorbent assay. Patient survival time was evaluated using univariate and multivariate analyses. Mass spectrometry and co-immunoprecipitation assays were utilized to discover proteins that interact with AEP. Gastric cancer cell lines were established, in which AEP was overexpressed or knocked out using lentiviral CRISPR. The proliferative abilities of these cell lines in response to chemotherapy agents were evaluated using the Cell Counting Kit-8 method. Gene expression changes in these lines were assessed by real-time polymerase chain reaction and Western blot.
Results: Patients with low expression of AEP were significantly more likely to have a good prognosis and experience complete response or partial response after treatment with docetaxel/S-1 regimen. Mass spectrum analysis showed that several proteins in the focal adhesion and mitogen-activated protein kinase signaling pathways interacted with AEP. IQGAP1 was confirmed to be one of the proteins interacting with AEP, and its protein level increased when AEP was knocked out. AEP knockout decreased resistance to microtubule inhibitors, including paclitaxel, docetaxel, and T-DM1. The expression levels of MDR1, p-EGFR, p-JNK, p-ERK, and p-Rac1/cdc42 were decreased in AEP knockout gastric cancer cell lines, and inhibitors of both JNK and ERK could block AEP-induced expression of MDR1.
Conclusion: AEP was not only a prognostic factor but also a predictive marker. AEP knockout could inhibit the activity of the EGFR/JNK/ERK signaling pathway and improve sensitivity to microtubule inhibitors through interacting with IQGAP1.

Keywords: Asparaginyl endopeptidase, MAP kinase signaling pathway, drug resistance, stomach cancer

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