Glutathionylation-dependent proteasomal degradation of wide-spectrum mutant p53 proteins by engineered zeolitic imidazolate framework-8

Zhang, Yunjiao; Huang, Xiaowan; Wang, Liansheng; Cao, Cong; Zhang, Hao; Wei, Pengfei; He, Dalin; Song, Yang; Chen, Ziying; Qian, Jiang; Zhong, Suqin; Liu, Zefeng; Wang, Meimei; Zhang, Wenbin; Jiang, Weihang; Zeng, Jie; Yao, Guangyu; Wen, Longping

doi:10.1016/j.biomaterials.2021.120720

Cited by 18 publications

(16 citation statements)

References 51 publications

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“…S13 ), indicating that neither Zn 2+ nor ROS released from Mn-ZnO 2 NPs altered the transcription of Mutp53 and the corresponding Mutp53 reduction most likely occurred through the post-translational degradation. Thus, the involvement of ubiquitination-mediated proteasome-degradation of Mutp53 [ 34 ] was verified using the MG132, a potent and cell-permeable proteasome inhibitor [ 59 ]. As shown in Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Following previous studies [ 23 , 34 ], the lysates of MDA-MB-231 cells after the treatment with Mn-ZnO 2 NPs without or with the presence of MG132 (10 μM) for 6 h were subjected to immunoprecipitation with BeaverBeads™ Protein A/G kit (BEAVER Biomedical, Suzhou, China) by using the antibody p53 (DO-1, 1 μg per sample). The pull-down complex was detected by western blotting with mutant p53 (ab32049, 1:1000 dilution), the Ubiquitin (ab134953, 1:1000 dilution) and K48-Ub (ab140601, 1:1000 dilution) antibodies.…”

Section: Methodsmentioning

confidence: 99%

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Carrier-free nanoprodrug for p53-mutated tumor therapy via concurrent delivery of zinc-manganese dual ions and ROS

Wang

Qu²,

Shao³

et al. 2023

Bioactive Materials

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Carrier-free nanoprodrug for p53-mutated tumor therapy via concurrent delivery of zinc-manganese dual ions and ROS

Wang

Qu²,

Shao³

et al. 2023

Bioactive Materials

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“…ZIF-8 was later improved using Z1-RGD peptide to exhibit higher stability and better internalization, as well as mutant p53 degradation ability. This modified ZIF-8 demonstrated promising therapeutic efficacy in breast cancer patient-derived xenograft (PDX) carrying p53 mutation [133]. Another means of degradation is through dietary glucose restriction.…”

Section: Inducing Mutant P53 Degradationmentioning

confidence: 99%

Role of p53 in breast cancer progression: An insight into p53 targeted therapy

Marvalim¹,

Datta²,

Lee³

2023

Theranostics

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The transcription factor p53 is an important regulator of a multitude of cellular processes. In the presence of genotoxic stress, p53 is activated to facilitate DNA repair, cell cycle arrest, and apoptosis. In breast cancer, the tumor suppressive activities of p53 are frequently inactivated by either the overexpression of its negative regulator MDM2, or mutation which is present in 30-35% of all breast cancer cases. Notably, the frequency of p53 mutation is highly subtype dependent in breast cancers, with majority of hormone receptor-positive or luminal subtypes retaining the wild-type p53 status while hormone receptor-negative patients predominantly carry p53 mutations with gain-of-function oncogenic activities that contribute to poorer prognosis. Thus, a two-pronged strategy of targeting wild-type and mutant p53 in different subtypes of breast cancer can have clinical relevance. The development of p53-based therapies has rapidly progressed in recent years, and include unique small molecule chemical inhibitors, stapled peptides, PROTACs, as well as several genetic-based approaches using vectors and engineered antibodies. In this review, we highlight the therapeutic strategies that are in pre-clinical and clinical development to overcome p53 inactivation in both wild-type and mutant p53-bearing breast tumors, and discuss their efficacies and limitations in pre-clinical and clinical settings.

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“…In addition, the stability of mutp53 protein is closely related to the redox state of the cells, and elevating oxidative state in the mutant p53 cells is another alternative approach to targeting mutp53 [ 23 ]. Recently, we have developed various nanoparticles [ 24 , 25 ], which exerted a remarkable increase of intracellular reactive oxygen species (ROS), to achieve cancer treatment effect by efficiently inducing mutp53 degradation, indicating that regulating ROS specifically in tumor cells was expected to solve the problem of mutp53 degradation. However, the nanoparticles previous reported as the mutp53 degraders identified so far oftentimes lacked sufficient specificity of elevating ROS in tumor cells, leading unfavorable toxicity in normal cells.…”

Section: Introductionmentioning

confidence: 99%

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

Zhang

et al. 2023

J Nanobiotechnol

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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.

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Glutathionylation-dependent proteasomal degradation of wide-spectrum mutant p53 proteins by engineered zeolitic imidazolate framework-8

Cited by 18 publications

References 51 publications

Carrier-free nanoprodrug for p53-mutated tumor therapy via concurrent delivery of zinc-manganese dual ions and ROS

Carrier-free nanoprodrug for p53-mutated tumor therapy via concurrent delivery of zinc-manganese dual ions and ROS

Role of p53 in breast cancer progression: An insight into p53 targeted therapy

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

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