Ubenimex induces autophagy inhibition and EMT suppression to overcome cisplatin resistance in GC cells by perturbing the CD13/EMP3/PI3K/AKT/NF-κB axis
Identifieur interne : 000296 ( Main/Exploration ); précédent : 000295; suivant : 000297Ubenimex induces autophagy inhibition and EMT suppression to overcome cisplatin resistance in GC cells by perturbing the CD13/EMP3/PI3K/AKT/NF-κB axis
Auteurs : Qie Guo [République populaire de Chine] ; Fan-Jing Jing [République populaire de Chine] ; Wen Xu [République populaire de Chine] ; Xiao Li [République populaire de Chine] ; Xin Li [République populaire de Chine] ; Jia-Lin Sun [République populaire de Chine] ; Xiao-Min Xing [République populaire de Chine] ; Chang-Kai Zhou [République populaire de Chine] ; Fan-Bo Jing [République populaire de Chine]Source :
- Aging (Albany NY) [ 1945-4589 ] ; 2019.
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.
Url:
DOI: 10.18632/aging.102598
PubMed: 31895687
PubMed Central: 6977684
Affiliations:
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Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003, PR China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Department of Clinical Pharmacy, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003</wicri:regionArea><wicri:noRegion>Shandong 266003</wicri:noRegion></affiliation></author><author><name sortKey="Sun, Jia Lin" sort="Sun, Jia Lin" uniqKey="Sun J" first="Jia-Lin" last="Sun">Jia-Lin Sun</name><affiliation wicri:level="1"><nlm:aff id="aff1">Department of Clinical Pharmacy, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003, PR China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Department of Clinical Pharmacy, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003</wicri:regionArea><wicri:noRegion>Shandong 266003</wicri:noRegion></affiliation></author><author><name sortKey="Xing, Xiao Min" sort="Xing, Xiao Min" uniqKey="Xing X" first="Xiao-Min" last="Xing">Xiao-Min Xing</name><affiliation wicri:level="1"><nlm:aff id="aff1">Department of Clinical Pharmacy, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003, PR China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Department of Clinical Pharmacy, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003</wicri:regionArea><wicri:noRegion>Shandong 266003</wicri:noRegion></affiliation></author><author><name sortKey="Zhou, Chang Kai" sort="Zhou, Chang Kai" uniqKey="Zhou C" first="Chang-Kai" last="Zhou">Chang-Kai Zhou</name><affiliation wicri:level="1"><nlm:aff id="aff1">Department of Clinical Pharmacy, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003, PR China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Department of Clinical Pharmacy, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003</wicri:regionArea><wicri:noRegion>Shandong 266003</wicri:noRegion></affiliation></author><author><name sortKey="Jing, Fan Bo" sort="Jing, Fan Bo" uniqKey="Jing F" first="Fan-Bo" last="Jing">Fan-Bo Jing</name><affiliation wicri:level="1"><nlm:aff id="aff1">Department of Clinical Pharmacy, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003, PR China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Department of Clinical Pharmacy, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003</wicri:regionArea><wicri:noRegion>Shandong 266003</wicri:noRegion></affiliation></author></analytic><series><title level="j">Aging (Albany NY)</title><idno type="eISSN">1945-4589</idno><imprint><date when="2019">2019</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>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.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct></listBibl></div1></back></TEI><affiliations><list><country><li>République populaire de Chine</li></country></list><tree><country name="République populaire de Chine"><noRegion><name sortKey="Guo, Qie" sort="Guo, Qie" uniqKey="Guo Q" first="Qie" last="Guo">Qie Guo</name></noRegion><name sortKey="Jing, Fan Bo" sort="Jing, Fan Bo" uniqKey="Jing F" first="Fan-Bo" last="Jing">Fan-Bo Jing</name><name sortKey="Jing, Fan Jing" sort="Jing, Fan Jing" uniqKey="Jing F" first="Fan-Jing" last="Jing">Fan-Jing Jing</name><name sortKey="Li, Xiao" sort="Li, Xiao" uniqKey="Li X" first="Xiao" last="Li">Xiao Li</name><name sortKey="Li, Xin" sort="Li, Xin" uniqKey="Li X" first="Xin" last="Li">Xin Li</name><name sortKey="Sun, Jia Lin" sort="Sun, Jia Lin" uniqKey="Sun J" first="Jia-Lin" last="Sun">Jia-Lin Sun</name><name sortKey="Xing, Xiao Min" sort="Xing, Xiao Min" uniqKey="Xing X" first="Xiao-Min" last="Xing">Xiao-Min Xing</name><name sortKey="Xu, Wen" sort="Xu, Wen" uniqKey="Xu W" first="Wen" last="Xu">Wen Xu</name><name sortKey="Zhou, Chang Kai" sort="Zhou, Chang Kai" uniqKey="Zhou C" first="Chang-Kai" last="Zhou">Chang-Kai Zhou</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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