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TRIM59 knockdown blocks cisplatin resistance in A549/DDP cells through regulating PTEN/AKT/HK2.

TRIM59 敲除通过调节PTEN/AKT/hk2 阻断A549/DDP细胞的顺铂耐药性。

  • 影响因子:0
  • DOI:10.1016/j.gene.2020.144553
  • 作者列表:"He R","Liu H
  • 发表时间:2020-07-15
Abstract

:Cisplatin is commonly used for lung cancer treatment. However, acquire resistance to cisplatin results in reduced therapy efficacy. Tripartite motif-containing 59 (TRIM59), acting as an oncogene in non-small cell lung cancer (NSCLC), induces chemoresistance in breast cancer cells. Here, the mechanism by which TRIM59 mediates cisplatin resistance was determined. We demonstrated that cisplatin-resistant NSCLC cell line (A549/DDP) had higher expression of TRIM59 than its parental cell line (A549). As indicated by cell apoptosis assay, TRIM59 overexpression in A549 cells resulted in an increased cisplatin resistance, while TRIM59 downregulation in A549/DDP cells led to an decreased cisplatin resistence. A549/DDP cells with TIMR59 knockdown was more sensitive to cisplatin treatment in a xenograft model. Moreover, A549/DDP cells exhibited increased glucose uptake, lactate production, and hexokinase 2 (HK2, an important glycolytic pathway enzyme) expression than A549 cells. The glycolysis was increased by TRIM59 overexpression in A549 cell, and decreased by TRIM59 knockdown in A549/DDP cells. 3-Bromopyruvate Acid (3-BrPA), an inhibitor of HK2, significantly enhanced cisplatin-sensitivity in A549 cells overexpressing TRIM59. Furthermore, both TRIM59 and HK2 expression was higher in cisplatin-resistant NSCLC tissues than in non-resistant ones, and mRNA expression of these two molecules was positively correlated in NSCLC tissues. The changes of PTEN and phosphorylation of AKT (p-AKT), a critical upstream regulator of HK2, were also consistent with HK2 expression. Immunoprecipiation experiments showed the interaction between TRIM59 and PTEN in A549/DDP cells, and that TRIM59 knockdown suppressed the ubiquitination of PTEN. Collectively, the present study indicates that TRIM59 knockdown reverses high glycolysis rate and cisplatin resistance in A549/DDP cells through the regulation of PTEN/AKT/HK2 and may provide insights into overcoming cancer resistance to cisplatin treatment.

摘要

: 顺铂常用于肺癌治疗。然而,获得对顺铂的抗性导致治疗功效降低。包含三方基序的 59 (TRIM59) 在非小细胞肺癌 (NSCLC) 中作为癌基因,诱导乳腺癌细胞的化学抗性。这里,确定了TRIM59 介导顺铂抗性的机制。我们证明顺铂抗性NSCLC细胞系 (A549/DDP) 比其亲代细胞系 (A549) 具有更高的TRIM59 表达。如细胞凋亡测定所示,在A549 细胞中TRIM59 过表达导致顺铂抗性增加,而在A549/DDP细胞中TRIM59 下调导致顺铂抗性降低。在异种移植模型中,敲除TIMR59 的A549/DDP细胞对顺铂处理更敏感。此外,A549/DDP细胞比A549 细胞表现出增加的葡萄糖摄取、乳酸产生和己糖激酶 2 (HK2,一种重要的糖酵解途径酶) 表达。在A549 细胞中,TRIM59 过表达增加了糖酵解,在A549/DDP细胞中,TRIM59 敲低了糖酵解。HK2 抑制剂 3-溴丙酮酸 (3-BrPA) 显著增强过表达trim59 的A549 细胞对顺铂的敏感性。此外,TRIM59 和HK2 在顺铂耐药NSCLC组织中的表达均高于非耐药NSCLC组织,并且这两种分子的mRNA表达在NSCLC组织中呈正相关。PTEN的变化和HK2 的关键上游调节因子AKT (p-AKT) 的磷酸化也与HK2 的表达一致。免疫排斥实验表明,在A549/DDP细胞中,TRIM59 和PTEN之间存在相互作用,并且TRIM59 敲除抑制了PTEN的泛素化。集体而言,本研究表明,TRIM59 敲除通过调节PTEN/AKT/HK2 逆转A549/DDP细胞的高糖酵解率和顺铂耐药性,并可能为克服顺铂治疗的癌症耐药性提供见解。

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影响因子:6.93
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DOI:10.1002/ijc.32532
作者列表:["Hata A","Nakajima T","Matsusaka K","Fukuyo M","Morimoto J","Yamamoto T","Sakairi Y","Rahmutulla B","Ota S","Wada H","Suzuki H","Matsubara H","Yoshino I","Kaneda A"]

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影响因子:6.93
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DOI:10.1002/ijc.32530
作者列表:["Zhang L","Yang Y","Chai L","Bu H","Yang Y","Huang H","Ran J","Zhu Y","Li L","Chen F","Li W"]

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肺肿瘤,又叫支气管肺癌,是常见的恶性肿瘤之一。肺肿瘤的治疗为包括手术、中药、放疗、化疗及免疫等多学科的综合治疗。

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