TRIM25 is associated with cisplatin resistance in non-small-cell lung carcinoma A549 cell line via downregulation of 14-3-3σ.
TRIM25 is associated with cisplatin resistance in non-small-cell lung carcinoma A549 cell line via downregulation of 14-3-3σ.
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DOI：
10.1016/j.bbrc.2017.08.151
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发表时间：
2017-11
影响因子：
3.1
通讯作者：
Xia Qin;F. Qiu;Zhen Zou
中科院分区：
文献类型：
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作者：
Xia Qin;F. Qiu;Zhen Zou
肺癌，特别是非小细胞肺癌（NSCLC）是癌症相关死亡的主要原因。顺铂（cisplatin，CDDP）作为NSCLC的一线化疗药物，但经常出现耐药情况。我们之前报道过，与亲代 A549 细胞相比，三联基序蛋白 25 (TRIM25) 在顺铂耐药人肺腺癌细胞 (A549/CDDP) 中高度表达。在此，我们进一步证明了 TRIM25 与顺铂耐药的关联及其潜在机制。在 A549/CDDP 细胞中通过 RNA 干扰敲低 TRIM25 可降低半数最大抑制浓度 (IC50) 值并促进顺铂响应的细胞凋亡，而 TRIM25 的过度表达则具有相反的作用。更重要的是，我们发现同时敲低14-3-3σ和TRIM25绝对逆转了单独敲低TRIM25引起的MDM2减少、p53增加、cleaved-Capsese3增加和IC50值降低，表明TRIM25主要通过14-3-3σ的下调介导顺铂耐药。我们的结果表明TRIM25与顺铂耐药相关，并且14-3-3σ-MDM2-p53信号通路参与了这一过程，表明靶向TRIM25可能是逆转顺铂耐药的潜在策略。
Lung cancer, in particular, non-small cell lung cancer (NSCLC), is the leading cause of cancer-related mortality.Cis-Diamminedichloroplatinum (cisplatin, CDDP) as first-line chemotherapy for NSCLC, but resistance occurs frequently. We previously reported that Tripartite motif protein 25 (TRIM25) was highly expressed in cisplatin-resistant human lung adenocarcinoma A549 cells (A549/CDDP) in comparison with its parental A549 cells. Herein, we take a further step to demonstrate the association of TRIM25 and cisplatin resistance and also the underlying mechanisms. Knockdown of TRIM25 by RNA interference in A549/CDDP cells decreased half maximal inhibitory concentration (IC50) values and promoted apoptosis in response to cisplatin, whereas overexpression of TRIM25 had opposite effects. More importantly, we found that concomitant knockdown of 14-3-3σ and TRIM25 absolutely reversed the decreased MDM2, increased p53, increased cleaved-Capsese3 and decreased IC50value induced by knockdown of TRIM25 individually, suggesting that TRIM25 mediated cisplatin resistance primarily through downregulation of 14-3-3σ. Our results indicate that TRIM25 is associated with cisplatin resistance and 14-3-3σ-MDM2-p53 signaling pathway is involved in this process, suggesting targeting TRIM25 may be a potential strategy for the reversal of cisplatin resistance.