Research Paper Volume 12, Issue 1 pp 80—105

Ubenimex induces autophagy inhibition and EMT suppression to overcome cisplatin resistance in GC cells by perturbing the CD13/EMP3/PI3K/AKT/NF-κB axis

Qie Guo 1, , Fan-Jing Jing 2, , Wen Xu 1, , Xiao Li 1, , Xin Li 1, , Jia-Lin Sun 1, , Xiao-Min Xing 1, , Chang-Kai Zhou 1, , Fan-Bo Jing 1, ,

  • 1 Department of Clinical Pharmacy, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003, PR China
  • 2 Department of Oncology, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003, PR China

received: May 8, 2019 ; accepted: December 2, 2019 ; published: December 31, 2019 ;

https://doi.org/10.18632/aging.102598
How to Cite

Copyright © 2020 Guo et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Cisplatin (CDDP)-based chemotherapy is a standard treatment for gastric cancer (GC). However, chemoresistance is a major obstacle for CDDP application. Exploring underlying mechanisms of CDDP resistance development in GC and selecting an effective strategy to overcome CDDP resistance remain a challenge. Here, we demonstrate that a transmembrane ectoenzyme, CD13, endows GC patients with insensitivity to CDDP and predicts an undesirable prognosis in GC patients with CDDP treatment. Similarly, CD13 expression is positively related with CDDP resistance in GC cells. A CD13 inhibitor, Ubenimex, reverses CDDP resistance and renders GC cells sensitivity to CDDP, for which CD13 reduction is essential, and epithelial membrane protein 3 (EMP3) is a putative target downstream of CD13. Furthermore, Ubenimex decreases EMP3 expression by boosting its CpG island hypermethylation for which CD13 down-regulation is required. In addition, EMP3 is a presumptive modifier by which CD13 exerts functions in the phosphoinositol 3-kinase/protein kinase B (PI3K/AKT) pathway. Ubenimex inhibits the activation of the CD13/EMP3/PI3K/AKT/NF-κB pathway to overcome CDDP resistance in GC cells by suppressing autophagy and epithelial-mesenchymal transition (EMT). Therefore, CD13 is a potential indicator of CDDP resistance formation, and Ubenimex may serve as a potent candidate for reversing CDDP resistance in GC.

Abbreviations

CDDP: Cisplatin; EMP3: Epithelial membrane protein 3; EMT: Epithelial-mesenchymal transition; PI3K/AKT: Phosphoinositol3-kinase/protein kinase B; IC50: half maximal inhibitory concentration; RIs: Resistance indices; IHC: Immunohistochemistry; CCK-8: Cell Counting Kit-8; Bcl-2: B-cell lymphoma 2; ZIPK: Zipper-interacting protein kinase; Co-IP: Co-immunoprecipitation; IHC: Immunohistochemistry; MS-PCR: Methylation-specific PCR.