Ubenimex induces autophagy inhibition and EMT suppression to overcome cisplatin resistance in GC cells by perturbing the CD13/EMP3/PI3K/AKT/NF-κB axis
Ubenimex induces autophagy inhibition and EMT suppression to overcome cisplatin resistance in GC cells by perturbing the CD13/EMP3/PI3K/AKT/NF-κB axis
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乌苯美司通过干扰CD13/EMP3/PI3K/AKT/NF-κB轴，诱导自噬抑制和上皮-间质转化抑制，从而克服胃癌细胞的顺铂耐药性。
DOI：
10.18632/aging.102598
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发表时间：
2020-01-15
期刊：
影响因子：
5.2
通讯作者：
Jing, Fan-Bo
中科院分区：
文献类型：
--
作者：
Guo, Qie;Jing, Fan-Jing;Jing, Fan-Bo
以顺铂(CDDP)为基础的化疗是胃癌的标准治疗方法。然而，化疗耐药是CDDP应用的主要障碍。探索胃癌顺铂耐药的潜在机制，选择有效的策略克服顺铂耐药仍然是一个挑战。在这里，我们证明了跨膜胞外酶CD13使GC患者对CDDP不敏感，并预测了接受CDDP治疗的GC患者的不良预后。同样，CD13的表达与胃癌细胞对顺铂的耐药性呈正相关。CD13抑制剂Ubenimex逆转了CDDP的耐药性，并使GC细胞对CDDP敏感，CD13的减少是必不可少的，上皮膜蛋白3(EMP3)可能是CD13下游的靶点。此外，Ubenimex通过促进其CpG岛超甲基化来降低EMP3的表达，而CD13的下调是必需的。此外，EMP3可能是CD13在PI3K/AKT途径中发挥作用的修饰物。Ubenimex通过抑制自噬和上皮-间充质转化(EMT)，抑制CD13/EMP3/PI3K/AKT/NF-kappa B通路的激活，从而克服GC细胞对CDDP的耐药。因此，CD13是CDDP耐药形成的潜在指标，而Ubenimex可能是逆转胃癌CDDP耐药的有效候选基因。
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-kappa B 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.