近日，南京大学沈燕研究团队发现天然化合物PEITC通过在p53和p73之间切换yap结合伙伴来抑制癌细胞中p53突变体的功能获得。这一研究成果发表在2025年2月10日出版的国际学术期刊《中国药理学报》上。

在这项研究中，该研究组研究了PEITC对携带多种p53突变的癌症中mtp53-YAP-p73相互作用的影响，但不限于结构突变。课题组发现，携带mtp53 （p53^R280K, p53^R273H）的乳腺癌、结直肠癌和肺癌细胞比携带wtp53的细胞对PEITC更敏感。

该课题组研究人员证明了PEITC在YAP的WW结合域与YAP结合，并诱导构象变化，促进YAP-mtp53复合物的解离，并抑制其在不同癌细胞中携带mtp53的促增殖转录活性。同时，PEITC作为分子胶增强YAP-p73复合物的关联，诱导细胞凋亡。这些结果为了解PEITC对多种癌症的抗癌活性提供了见解，并突出了基于PEITC的癌症治疗的独特作用模式。

据悉，从十字花系蔬菜中提取的异硫氰酸苯乙酯（PEITC）通过调节细胞凋亡、细胞周期阻滞、药物代谢酶，甚至优先恢复p53^R175H的“WT样”构象，显示出抗癌活性。但其分子抗癌机制尚不清楚。有证据表明，将YAP结合伙伴从促肿瘤蛋白转变为促凋亡蛋白，可能对治疗携带mtp53的人类癌症具有很大的潜力。

附：英文原文

Title: Natural compound PEITC inhibits gain of function of p53 mutants in cancer cells by switching YAP-binding partners between p53 and p73

Author: Wang, Yi-xuan, Wang, Li-wei, Huang, Ying, Zhou, Lin, Li, Guo-yu, Yang, Jia-wen, Wu, Xue-feng, Cheng, Jing-cai, Xu, Qiang, Shen, Yan

Issue&Volume: 2025-02-10

Abstract: Phenethyl isothiocyanate (PEITC) derived from cruciferous vegetables has shown anticancer activities by modulating apoptosis, cell cycle arrest, drug-metabolizing enzymes and even preferentially restoring a ‘WT-like’ conformation to p53^R175H. But its molecular anti-cancer mechanisms are not well understood. Evidence shows that switching YAP-binding partners from pro-tumorigenic to pro-apoptotic proteins might hold great potential for the treatment of human cancers harboring mtp53. In this study we investigated the impact of PEITC on mtp53-YAP-p73 interaction in cancers harboring a variety of p53 mutants, but not limited to structural mutations. We showed that breast cancer, colorectal and lung cancer cells harboring mtp53 (p53^R280K, p53^R273H) were more sensitive to PEITC than those cells harboring wtp53. We demonstrated that PEITC bound to YAP at its WW binding domain, and induced a conformational change, facilitated the dissociation of YAP-mtp53 complex and inhibited their pro-proliferative transcriptional activity in different cancer cells harboring mtp53. Concomitantly, PEITC acted as a molecular glue to enhance the association of YAP-p73 complex and induced apoptosis. These results provide insights into the anticancer activity of PEITC against a wide spectrum of cancers and highlight a unique mode of action for PEITC-based cancer therapy.

DOI: 10.1038/s41401-025-01474-1

Source: https://www.nature.com/articles/s41401-025-01474-1