Precise pancreatic cancer therapy through targeted degradation of mutant p53 protein by cerium oxide nanoparticles
Hao Zhang1, Wang Zhang1, Bochuan Hu2
1School of Medicine, South China University of Technology, Guangzhou, 510006, P. R. China.
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.
Insights
Cerium oxide nanoparticles (CeO2 NPs) specifically target and degrade mutant p53 proteins in cancer cells by increasing reactive oxygen species (ROS). This targeted approach reduces tumor growth and migration, offering a promising strategy for p53-mutated cancers.
Area of Science:
- Nanomedicine
- Cancer Biology
- Biochemistry
Background:
- Point mutations in the TP53 gene are common in many cancers, leading to tumor-promoting mutant p53 (mutp53) proteins.
- Targeting mutp53 for degradation via autophagy or proteasomal pathways is a potential cancer therapy strategy.
- Previous attempts to elevate oxidative stress in tumor cells using nanoparticles lacked specificity, causing toxicity in healthy cells.
Purpose of the Study:
- To investigate the potential of cerium oxide nanoparticles (CeO2 NPs) for specifically targeting and degrading mutp53 in cancer cells.
- To elucidate the mechanism by which CeO2 NPs induce mutp53 degradation.
- To evaluate the therapeutic efficacy of CeO2 NPs in a preclinical cancer model.
Main Methods:
- Treatment of cancer cells and a tumor model with CeO2 NPs.
- Measurement of reactive oxygen species (ROS) production.
- Analysis of mutp53 protein levels, ubiquitination, and dissociation from heat shock proteins (Hsp90/70).
- Assessment of cell proliferation, migration, and tumor growth.
Main Results:
- CeO2 NPs significantly increased ROS production specifically in tumor cells compared to healthy cells.
- CeO2 NPs induced K48 ubiquitination-dependent degradation of mutp53 proteins.
- Degradation of mutp53 by CeO2 NPs abrogated its gain-of-function, reducing cell proliferation and migration.
- CeO2 NPs demonstrated improved therapeutic efficacy in a BxPC-3 mutp53 tumor model.
Conclusions:
- CeO2 NPs exhibit specific therapeutic efficacy against mutp53 cancer cells by selectively increasing ROS.
- CeO2 NPs promote mutp53 degradation through a mechanism involving ROS production and dissociation from Hsp90/70.
- CeO2 NPs offer a promising and specific strategy for targeting cancers with TP53 mutations.
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