MI-773, a breaker of the MDM2/p53 axis, exhibits anticancer effects in neuroblastoma via downregulation of INSM1
MI-773, a breaker of the MDM2/p53 axis, exhibits anticancer effects in neuroblastoma via downregulation of INSM1
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MI-773 是 MDM2/p53 轴的破坏者，通过下调 INSM1 在神经母细胞瘤中表现出抗癌作用。
DOI：
10.3892/ol.2021.13099
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发表时间：
2021-12-01
期刊：
影响因子：
2.9
通讯作者：
Pan, Jian
中科院分区：
文献类型：
--
作者：
Chen, Yan-Ling;Zhang, Zi-Mu;Pan, Jian
神经母细胞瘤（NB）是一种常见的儿科恶性肿瘤与不良后果。最近的研究表明，小鼠双微体2同源物（MDM 2）蛋白抑制剂是有前途的抗癌药物。MI-773是一种新的MDM 2特异性拮抗剂，但其抗NB活性的分子机制尚不清楚。在MI-773处理后，通过细胞计数试剂盒-8测定来测量NB细胞活力。用PI染色分析细胞周期进程，用Annexin V/PI染色评估细胞凋亡。使用微阵列研究MI-773发挥其作用的分子机制。结果表明，MI-773对MDM 2/p53轴的干扰导致NB细胞的增殖抑制、诱导凋亡和细胞周期阻滞。此外，微阵列分析显示，MI-773导致参与G2/M期检查点的基因显著下调和与p53通路相关的hallmark基因上调。同时，胰岛素瘤相关蛋白1的敲低降低NB细胞的增殖，增加凋亡。总之，本研究表明，MI-773对MDM 2和TP 53之间的相互作用具有高选择性和阻断亲和力，并可能作为治疗NB的新策略。
Neuroblastoma (NB) is a common pediatric malignancy associated with poor outcomes. Recent studies have shown that murine double minute2 homolog (MDM2) protein inhibitors are promising anticancer agents. MI-773 is a novel and specific antagonist of MDM2, however, the molecular mechanism of its anti-NB activity remains unclear. NB cell viability was measured by Cell Counting Kit-8 assay following MI-773 treatment. Cell cycle progression was analyzed using PI staining and apoptosis was assessed using Annexin V/PI staining. The molecular mechanisms by which MI-773 exerted its effects were investigated using a microarray. The results showed that disturbance of the MDM2/p53 axis by MI-773 resulted in potent suppression of proliferation, induction of apoptosis and cell cycle arrest in NB cells. In addition, microarray analysis showed that MI-773 led to significant downregulation of genes involved in the G2/M phase checkpoint and upregulation of hallmark gene associated with the p53 pathway. Meanwhile, knockdown of insulinoma-associated 1 decreased proliferation and increased apoptosis of NB cells. In conclusion, the present study demonstrated that MI-773 exhibited high selectivity and blockade affinity for the interaction between MDM2 and TP53 and may serve as a novel strategy for the treatment of NB.