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

摘要

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.