蜗牛
心理压抑
转移
癌症研究
化学
小分子
细胞周期蛋白依赖激酶2
细胞生物学
激酶
生物
内科学
医学
生物化学
蛋白激酶A
癌症
生态学
基因
基因表达
作者
Boxue Ren,Yahui Li,Lijun Di,Ruochuan Cheng,Lijuan Liu,Hongmei Li,Yang Li,Zhao-ying Tang,Yong‐Ming Yan,Tao Lü,Rong Fu,Yong‐Xian Cheng,Zhao-Qiu Wu
标识
DOI:10.1016/s1875-5364(24)60550-9
摘要
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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