MI‑773, a breaker of the MDM2/p53 axis, exhibits anticancer effects in neuroblastoma via downregulation of INSM1
Yanling Chen, Zi-Mu Zhang, Xiaolu Li, Yanfang Tao, Shuiyan Wu, Fang Fang, Yi Xie, Xinmei Liao, Gen Li, Di Wu, Hairong Wang, Ran Zuo, Haibo Cao, Jingjing Pan, Juanjuan Yu, Zheng Zhang, Xinran Chu, Yongping Zhang, Chenxi Feng, Jianwei Wang, Jun Lü, Shaoyan Hu, Zhiheng Li, Jian Pan
Abstract
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 G<sub>2</sub>/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.