Resveratrol prevents p53 aggregation in vitro and in breast cancer cells

Abstract

One potential target for cancer therapeutics is the tumor suppressor p53, which is mutated in more than 50% of malignant tumors. Loss of function (LoF), dominant negative (DN) and gain of function (GoF) mutations in p53 are associated with amyloid aggregation. We tested the potential of resveratrol, a naturally occurring polyphenol, to interact and prevent the aggregation of wild-type and mutant p53 in vitro using fluorescence spectroscopy techniques and in human breast cancer cells (MDA-MB-231, HCC-70 and MCF-7) using immunofluorescence co-localization assays. Based on our data, an interaction occurs between resveratrol and the wild-type p53 core domain (p53C). In addition, resveratrol and its derivatives pterostilbene and piceatannol inhibit mutant p53C aggregation in vitro. Additionally, resveratrol reduces mutant p53 protein aggregation in MDA-MB-231 and HCC-70 cells but not in the wild-type p53 cell line MCF-7. To verify the effects of resveratrol on tumorigenicity, cell proliferation and cell migration assays were performed using MDA-MB-231 cells. Resveratrol significantly reduced the proliferative and migratory capabilities of these cells. Our study provides evidence that resveratrol directly modulates p53, enhancing our understanding of the mechanisms involved in p53 aggregation and its potential as a therapeutic strategy for cancer treatment.

The Status of p53 Oligomeric and Aggregation States in Cancer

“…Due to the high number of destabilizing p53 DBD mutations, a more general solution could be advantageous. PRIMA-1 and resveratrol are possible candidate molecules to this end [80,81]. In the case of PRIMA-1, our group evidenced the molecular mechanism through which the compound rescues amyloid aggregates of mutant p53 and thereby decreases the dominant negative (DN) and gain-of-function (GoF) effects [80], indicating that mutant p53 aggregation is an exceptional target for the development of new drugs against cancer.…”

Follow the Mutations: Toward Class-Specific, Small-Molecule Reactivation of p53

“…Evidence suggests that PK083 [31] and ZMC1 [52] indeed produce this effect. In addition to these synthetic molecules, natural products including DNA [69,70], RNA [71], polyarginine [72], and the plant phenol resveratrol [73] have been shown to suppress or otherwise modulate p53 aggregation. In any case, it seems likely that the combination of aggregation inhibitors with class-specific reactivators will be an especially fruitful therapeutic strategy.…”

Recent Synthetic Approaches towards Small Molecule Reactivators of p53

“…It is important to note that among all of the small molecules capable of restoring the function of p53, this natural product is the only one that does not bear a nitrogen atom. Resveratrol is another molecule that has shown to inhibit the aggregation of p53 mutants in vitro, in tumor cells and in xenotransplants implanted in a nude mouse model [91]. High doses of resveratrol (100 µM) were required to exert the anti-amyloid and antitumoral effects.…”