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.
Highlights
In recent decades, cancer has emerged as a major public health problem, and approximately 13 million cancer-related deaths are estimated to occur worldwide by 2030 [1,2,3]
P53C is primarily known as a DNAbinding domain, other molecules interact with this region of the protein [43]
Because p53 has been implicated in the anticancer properties of resveratrol, we examined whether this bioactive compound directly modulates p53 core domain (p53C) by promoting changes in tyrosine fluorescence intensity
Summary
Cancer has emerged as a major public health problem, and approximately 13 million cancer-related deaths are estimated to occur worldwide by 2030 [1,2,3]. The intracellular aggregation of mutant p53 protein has been shown to inactivate p53, aggravating or inducing malignancy [9,10,11,12,13,14,15]. As shown in our previous studies, wild-type and mutant p53 core domains form β-sheet-rich fibrillar aggregates under mild denaturing conditions. These aggregates exert a cytotoxic effect on cultured macrophages [16]. A mutant form of p53 co-localizes with amyloid-like protein aggregates in breast cancer biopsies and in tumor cell lines [13]. P53 aggregation may participate in some cancers through a mechanism similar to amyloid diseases
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