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

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 challe...

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Autores principales: Guo, Qie, Jing, Fan-Jing, Xu, Wen, Li, Xiao, Li, Xin, Sun, Jia-Lin, Xing, Xiao-Min, Zhou, Chang-Kai, Jing, Fan-Bo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6977684/
https://www.ncbi.nlm.nih.gov/pubmed/31895687
http://dx.doi.org/10.18632/aging.102598
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author Guo, Qie
Jing, Fan-Jing
Xu, Wen
Li, Xiao
Li, Xin
Sun, Jia-Lin
Xing, Xiao-Min
Zhou, Chang-Kai
Jing, Fan-Bo
author_facet Guo, Qie
Jing, Fan-Jing
Xu, Wen
Li, Xiao
Li, Xin
Sun, Jia-Lin
Xing, Xiao-Min
Zhou, Chang-Kai
Jing, Fan-Bo
author_sort Guo, Qie
collection PubMed
description 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.
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spelling pubmed-69776842020-01-31 Ubenimex induces autophagy inhibition and EMT suppression to overcome cisplatin resistance in GC cells by perturbing the CD13/EMP3/PI3K/AKT/NF-κB axis Guo, Qie Jing, Fan-Jing Xu, Wen Li, Xiao Li, Xin Sun, Jia-Lin Xing, Xiao-Min Zhou, Chang-Kai Jing, Fan-Bo Aging (Albany NY) Research Paper 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. Impact Journals 2019-12-31 /pmc/articles/PMC6977684/ /pubmed/31895687 http://dx.doi.org/10.18632/aging.102598 Text en Copyright © 2020 Guo et al. http://creativecommons.org/licenses/by/3.0/ 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.
spellingShingle Research Paper
Guo, Qie
Jing, Fan-Jing
Xu, Wen
Li, Xiao
Li, Xin
Sun, Jia-Lin
Xing, Xiao-Min
Zhou, Chang-Kai
Jing, Fan-Bo
Ubenimex induces autophagy inhibition and EMT suppression to overcome cisplatin resistance in GC cells by perturbing the CD13/EMP3/PI3K/AKT/NF-κB axis
title Ubenimex induces autophagy inhibition and EMT suppression to overcome cisplatin resistance in GC cells by perturbing the CD13/EMP3/PI3K/AKT/NF-κB axis
title_full Ubenimex induces autophagy inhibition and EMT suppression to overcome cisplatin resistance in GC cells by perturbing the CD13/EMP3/PI3K/AKT/NF-κB axis
title_fullStr Ubenimex induces autophagy inhibition and EMT suppression to overcome cisplatin resistance in GC cells by perturbing the CD13/EMP3/PI3K/AKT/NF-κB axis
title_full_unstemmed Ubenimex induces autophagy inhibition and EMT suppression to overcome cisplatin resistance in GC cells by perturbing the CD13/EMP3/PI3K/AKT/NF-κB axis
title_short Ubenimex induces autophagy inhibition and EMT suppression to overcome cisplatin resistance in GC cells by perturbing the CD13/EMP3/PI3K/AKT/NF-κB axis
title_sort ubenimex induces autophagy inhibition and emt suppression to overcome cisplatin resistance in gc cells by perturbing the cd13/emp3/pi3k/akt/nf-κb axis
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6977684/
https://www.ncbi.nlm.nih.gov/pubmed/31895687
http://dx.doi.org/10.18632/aging.102598
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