Enhancing Chemotherapy of p53‐Mutated Cancer through Ubiquitination‐Dependent Proteasomal Degradation of Mutant p53 Proteins by Engineered ZnFe‐4 Nanoparticles

Abstract

A significant percentage of human cancers harbor missense mutations in the TP53 gene and express highly stabilized mutant p53 protein (mutp53) with tumor‐promoting gain‐of‐function (GOF) properties. Inducing mutp53 degradation is a viable precision anti‐tumor therapeutic strategy. Based on the previously reported finding that a zinc‐curcumin compound induced mutp53 degradation, a series of ZnFe nanoparticles (ZnFe NPs) are synthesized and it is found that ZnFe‐4, with an Zn:Fe ratio of 1:2, exhibits outstanding mutp53‐degrading capability. ZnFe‐4 induced ubiquitination‐mediated proteasomal degradation of several different mutp53 species, but not the wild‐type p53 protein. Cellular internalization, intracellular Zn++ elevation and increased ROS are all necessary for ZnFe‐4‐induced mutp53 degradation. Degradation of mutp53 by ZnFe‐4, abrogated mutp53‐manifested GOF, leading to increased p21 expression, cell cycle arrest, reduced cell proliferation and cell migration, and cell demise. ZnFe‐4 also sensitized to cisplatin‐elicited killing in p53 S241F ES‐2 ovarian cancer cells, and dramatically improved the therapeutic efficacy of cisplatin in a subcutaneous ES‐2 tumor model. The potential clinical utility of ZnFe‐4 is further demonstrated in an orthotopically‐implanted p53 Y220C patient‐derived xenograft (PDX) breast cancer model. ZnFe‐4 is the first reported mutp53‐degrading nanomaterial, and further materials engineering may lead to the development of zinc‐based nanoparticles with minimal toxicity and maximized mutp53‐degrading capability.

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

“…In addition, Mn-ZnO 2 NP-induced degradation of mutp53 and wild-type p53 accumulation in MDA-MB-231 cells also caused the cell cycle arrest at the G2M phase ( Fig. S18 ), consistent with previous evidence [ 23 ]. Taken together, the obtained results demonstrated that Mn-ZnO 2 NPs could induce Mutp53 degradation via the released Zn 2+ and ROS, activate WTp53 mainly via the released Mn 2+ , and promote cytotoxic •OH generation via the Fenton reaction, which synergistically eradicated the p53-mutated tumor cells.…”

“…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.…”

“…Recently, Chen and co-workers reported that zinc ions (Zn 2+ ) could inhibit the mitochondrial electron transport chain (mETC) and promote the production of reactive oxygen species (ROS) (such as O 2 · - and H 2 O 2 ) by increasing electron leakage to the oxygen at NADH-Q reductase (complex I) and ubiquinol-cytochrome-c reductase (complex III) of mETC [ 22 ]. More importantly, elevated intracellular Zn 2+ level and endogenous ROS generation exhibit the capability of selectively degrading a panel of Mutp53 (both contact and conformational mutation), but not the WTp53, via the ubiquitination-mediated proteasomal (UPS) pathway [ 23 ]. Such observations partially prop our hypothesis that endogenous generation of ROS through Zn 2+ in combination with exogenous supply of ROS would lead to more effective Mutp53 degradation.…”

Magnetic Metal Micelles for Enhanced Delivery of Self-Immolating CD8+ T-Cell Epitopes for Cancer Immunotherapy

“…41,42 Furthermore, some metal-based materials with optical and paramagnetic properties can be used as contrast agents to image and track the delivery process of the vaccine. 43 Although the low sensitivity of magnetic resonance (MR) imaging (MRI) using Fe 3 O 4 is one concern for the applications of tumor theranostics, 44,45 doping with zinc ions in Fe 3 O 4 has been explored to improve the paramagnetism of nanoparticles. 43,46 Taking the aforementioned points together, we designed a multifunctional magnetic anticancer nanovaccine that can generate an enhanced CD8 + T-cell response for targeting delivery mediated by an external magnetic field.…”

“…43 Although the low sensitivity of magnetic resonance (MR) imaging (MRI) using Fe 3 O 4 is one concern for the applications of tumor theranostics, 44,45 doping with zinc ions in Fe 3 O 4 has been explored to improve the paramagnetism of nanoparticles. 43,46 Taking the aforementioned points together, we designed a multifunctional magnetic anticancer nanovaccine that can generate an enhanced CD8 + T-cell response for targeting delivery mediated by an external magnetic field. Dual adjuvants, including imiquimod and inorganic Zn 1.15 Fe 1.85 O 4 , were coencapsulated in the Pluronic F127 block copolymer.…”