Precise pancreatic cancer therapy through targeted degradation of mutant p53 protein by cerium oxide nanoparticles

Abstract

Background In a significant proportion of cancers, point mutations of TP53 gene occur within the DNA-binding domain, resulting in an abundance of mutant p53 proteins (mutp53) within cells, which possess tumor-promoting properties. A potential and straightforward strategy for addressing p53-mutated cancer involves the induction of autophagy or proteasomal degradation. Based on the previously reported findings, elevating oxidative state in the mutp53 cells represented a feasible approach for targeting mutp53. However, the nanoparticles previous reported lacked sufficient specificity of regulating ROS in tumor cells, consequently resulted in unfavorable toxicity in healthy cells. Results We here in showed that cerium oxide CeO2 nanoparticles (CeO2 NPs) exhibited an remarkable elevated level of ROS production in tumor cells, as compared to healthy cells, demonstrating that the unique property of CeO2 NPs in cancer cells provided a feasible solution to mutp53 degradation. CeO2 NPs elicited K48 ubiquitination-dependent degradation of wide-spectrum mutp53 proteins in a manner that was dependent on both the dissociation of mutp53 from the heat shock proteins Hsp90/70 and the increasing production of ROS. As expected, degradation of mutp53 by CeO2 NPs abrogated mutp53-manifested gain-of-function (GOF), leading to a reduction in cell proliferation and migration, and dramatically improved the therapeutic efficacy in a BxPC-3 mutp53 tumor model. Conclusions Overall, CeO2 NPs increasing ROS specifically in the mutp53 cancer cells displayed a specific therapeutic efficacy in mutp53 cancer and offered an effective solution to address the challenges posed by mutp53 degradation, as demonstrated in our present study.

Reactive oxygen species nanoamplifiers with multi-enzymatic activities for enhanced tumor therapy

“…According to the previously reported literature studies on in vivo cancer therapy, the total dosage of SSA ranged from 5 to 10 mg kg −1 , 37,38 while the dosage of CeO 2 used ranged from 5 to 30 mg kg −1 . 39,40 Herein, the total dosage of SSA (3 × 1.4 mg kg −1 ) and Ce (3 × 5 mg kg −1 ) is significantly lower than the reported maximum dosage. The 4T1 tumor-bearing Balb/c mice were randomly divided into 4 groups (5 mice per group) with different treatments: (1) PBS, (2) SSA, (3) Ce-HMSN–PEG and (4) SSA@Ce-HMSN–PEG.…”

Targeting mutant p53 stabilization for cancer therapy

“…Zeolite imidazolate framework-8 (ZIF-8), a non-toxic and biocompatible nanomaterial consisting of zinc ions as metal nodes and 2-methylimidazolate as a junction molecule, exhibited extensive mutant p53 degradation. This performance was attributed to the material characteristics of ZIF-8, where ZIF-8 catabolism in acidic endosomes sustained elevated intracellular Zn and decreased intracellular GSH:GSSG ratio which in turn led to enhanced mutant p53 glutathionization and ultimately polyubiquitination and mutant p53 degradation ( Zhang et al, 2021 ); Cerium oxide nanoparticles induce a K48 ubiquitination-dependent degradation of broad-spectrum mutant p53 protein, that is, dependent on dissociation of mutant p53 protein from heat shock protein Hsp90/70 and an increase in reactive oxygen species (ROS) ( Zhang et al, 2023 ).…”

NIR triggered polydopamine coated cerium dioxide nanozyme for ameliorating acute lung injury via enhanced ROS scavenging

“…Recent CeO 2 based nanosystems for diseases therapy mainly rely on forming combined nanoplatforms by conjugating them with targeted ligands [17], photosensitizers [18] and therapeutic drugs [19]. Promisingly, not just as drug carriers, CeO 2 could act as hybrid enzymes-like therapeutic agents, such as converting •O 2 − to O 2 [20], or inducing ROS formation with external stimuli [21]. To further strengthen its catalytic activities, CeO 2 was also engineered designed to generate rich defects by doping different metal or metal oxide including Au [16], Pt [22], Ru [23], Cu [24], Mn [25] etc., or different polymer materials (polyvinylpyrrolidone (PVP) [26], polymethyl methacrylate (PMMA) [27], polyaniline (PANI) [28] etc.).…”