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

Boxue REN; Yang LI; Lei DI; Ranran CHENG; Lijuan LIU; Hongmei LI; Yi LI; Zhangrui TANG; Yongming YAN; Tao LU; Rong FU; Yongxian CHENG; Zhaoqiu WU

doi:10.1016/S1875-5364(24)60550-9

Chinese Journal of Natural Medicines ›› 2024, Vol. 22 ›› Issue (2) :112 -126. DOI: 10.1016/S1875-5364(24)60550-9

Original article

research-article

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

Boxue REN ¹^,^∆
, Yang LI ¹^,^∆
, Lei DI ¹^,^∆
, Ranran CHENG ¹^,^∆
, Lijuan LIU ¹
, Hongmei LI ¹
, Yi LI ¹
, Zhangrui TANG ¹
, Yongming YAN ²
, Tao LU ¹
, Rong FU ¹^,^*
, Yongxian CHENG ²^,^*
, Zhaoqiu WU ¹^,^*

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Abstract

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.

Keywords

LZ22, Wild-type p53 / p53 Reactivator / Snail-driven EMT / Tumor growth and metastasis

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Boxue REN, Yang LI, Lei DI, Ranran CHENG, Lijuan LIU, Hongmei LI, Yi LI, Zhangrui TANG, Yongming YAN, Tao LU, Rong FU, Yongxian CHENG, Zhaoqiu WU. 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. Chinese Journal of Natural Medicines, 2024, 22(2): 112-126 DOI:10.1016/S1875-5364(24)60550-9

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