REN Boxue, LI Yang, DI Lei, CHENG Ranran, LIU Lijuan, LI Hongmei, LI Yi, TANG Zhangrui, YAN Yongming, LU Tao, FU Rong, CHENG Yongxian, WU Zhaoqiu. A naturally derived small molecule compound suppresses tumor growth and metastasis in mice by relieving p53-dependent repression of CDK2/Rb signaling and the Snail-driven EMT [J].Chin J Nat Med, 2024, 22(2): 112-126. doi: 10.1016/S1875-5364(24)60550-9
Citation: REN Boxue, LI Yang, DI Lei, CHENG Ranran, LIU Lijuan, LI Hongmei, LI Yi, TANG Zhangrui, YAN Yongming, LU Tao, FU Rong, CHENG Yongxian, WU Zhaoqiu. A naturally derived small molecule compound suppresses tumor growth and metastasis in mice by relieving p53-dependent repression of CDK2/Rb signaling and the Snail-driven EMT [J].Chin J Nat Med, 2024, 22(2): 112-126. doi: 10.1016/S1875-5364(24)60550-9

A naturally derived small molecule compound suppresses tumor growth and metastasis in mice by relieving p53-dependent repression of CDK2/Rb signaling and the Snail-driven EMT

  • The tumor suppressor protein p53 is central to cancer biology, with its pathway reactivation emerging as a promising therapeutic strategy in oncology. This study introduced LZ22, a novel compound that selectively inhibits the growth, migration, and metastasis of tumor cells expressing wild-type p53, demonstrating ineffectiveness in cells devoid of p53 or those expressing mutant p53. LZ22’s mechanism of action involves a high-affinity interaction with the histidine-96 pocket of the MDM2 protein. This interaction disrupted the MDM2-p53 binding, consequently stabilizing p53 by shielding it from proteasomal degradation. LZ22 impeded cell cycle progression and diminished cell proliferation by reinstating the p53-dependent suppression of the CDK2/Rb signaling pathway. Moreover, LZ22 alleviated the p53-dependent repression of Snail transcription factor expression and its consequent EMT, effectively reducing tumor cell migration and distal metastasis. Importantly, LZ22 administration in tumor-bearing mice did not manifest notable side effects. The findings position LZ22 as a structurally unique reactivator of p53, offering therapeutic promise for the management of human cancers with wild-type TP53.
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