Glutathionylation-dependent proteasomal degradation of wide-spectrum mutant p53 proteins by engineered zeolitic imidazolate framework-8. (April 2021)

• Record Type: Journal Article
• Authors: Zhang, Yunjiao; Huang, Xiaowan; Wang, Liansheng; Cao, Cong; Zhang, Hao; Wei, Pengfei; Ding, He; Song, Yang; Chen, Ziying; Qian, Jieying; Zhong, Suqin; Liu, Zefeng; Wang, Meimei; Zhang, Wenbin; Jiang, Wenwei; Zeng, Jie; Yao, Guangyu; Wen, Long-ping
• Is Part Of: Biomaterials. Volume 271(2021)
• Publication Date: 2021-04
• Subjects: Mutant p53 -- Proteasomal degradation -- Glutathionylation -- Zeolitic imidazolate framework-8 -- Decomposition -- Zn++ -- Cancer therapy; Biomedical materials -- Periodicals; Biocompatible Materials -- Periodicals; Biomatériaux -- Périodiques; 610.28
• DOI: 10.1016/j.biomaterials.2021.120720
• Languages: English
• ISSNs: 0142-9612

Abstract

Abstract: Point mutations within the DNA-binding domain of the TP53 gene occur in a significant percentage of human cancer, leading to cellular accumulation of highly stabilized mutant p53 proteins (mutp53) with tumor-promoting properties. Depletion of mutp53, through inducing either autophagic or proteasomal degradation, is an attractive strategy for the therapy of p53-mutated cancer, but the currently-known degradation inducers, almost exclusively small molecules, are inadequate. Here we show that pH-responsive zeolitic imidazolate framework-8 (ZIF-8) offers a novel solution to mutp53 degradation. ZIF-8 facilitated ubiquitination-mediated and glutathionylation-dependent proteasomal degradation of all of the nine mutp53 we tested, including six hot-spot mutp53, but not the wild-type p53 protein. Sustained elevation of intracellular Zn ++ level, resulted from decomposition of the internalized ZIF-8 in the acidic endosomes, decreased the intracellular reduced glutathione (GSH): oxidized glutathione (GSSG) ratio and was essential for mutp53 glutathionylation and degradation. ZIF-8 modified with an Z1-RGD peptide, exhibiting enhanced cellular internalization and improved decomposition behavior, preferentially killed mutp53-expressing cancer cells and demonstrated remarkable therapeutic efficacy in a p53 S241F ES-2 ovarian cancer model as well as in a p53 Y220C patient-derived xenograft (PDX) breast cancer model. The ability to induce wide-spectrum mutp53 degradation gives ZIF-8 a clear advantage over other degradation-inducers, and engineered nanomaterials may be promising alternatives to small molecules for the development of mutp53-targeting drugs. Graphical abstract: Image 1