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.

Among other functions, p53 acts as a transcription factor and is involved in cell cycle control, leading to apoptosis or to the arrest of the cell cycle for DNA damage repair. It is mutated in around 50% of all tumors. In general, mutations occur on the DNA‐binding domain, leading to its loss of function as a transcription factor. It has been postulated that mutant p53 can form aggregates that are related to loss‐of‐function and cancer development. Also, new data have contributed to the spread the application of the prion concept on different amyloid diseases. In this work, we show that the effect of mutant p53 on wild type p53 aggregation occurs in a prion‐like fashion. We have also observed that resveratrol, a natural polyphenol known for its p53 activation properties, and PRIMA‐1, a classical stabilizer and reactivator of mutant p53 structure and function, exert their effects on aggregated mutant p53. Also, resveratrol and 2‐methylene‐3‐quinuclidinone hydrate (MQ), the major PRIMA‐1 active metabolite, have been shown to inhibit WT and mutant p53 core domain (p53C) aggregation at 37oC. The p53 WT form has been protected in a lower degree. MQ has also been shown to inhibit the seeding promoted by mutant p53 cellular extract on WTp53C. The same seeding inhibition effect was observed for extracts from cells treated with PRIMA‐1. Altogether, these findings indicate that prion‐like aggregation of p53 is a good therapeutic target in cancer. Supported by FAPERJ and CNPq.

Pterostilbene and piceatannol, two derivatives of resveratrol, are bioactive food compounds that mediates many cellular targets involved in cancer signaling pathways. The p53 tumor suppressor protein plays an essential role in preventing cancer development by inducing cell cycle arrest or apoptosis in response to cellular stress. This protein has been suggested to have a role in the anticancer properties of resveratrol and its structural analogues. Thus, the present study was aimed to check the cytotoxic and pro‐apoptotic effects of pterostilbene and piceatannol on human breast cancer cells. MTT reduction cell viability assays showed that resveratrol derivatives (0‐100 µM) promoted a cytotoxic effect on MCF‐7 and MDA‐MB‐231 breast cancer cells in a dose‐ and time‐dependent manner. The effects induced by pterostilbene were more pronounced than those triggered by piceatannol in both cell lines. Furthermore, cell treatment with 100 µM of pterostilbene for 24h increased phosphatidylserine exposure on cell surface, which is suggestive of apoptosis. This effect was partially prevented when cells were pretreated with pifithrin‐α, a specific p53 inhibitor. Taken together, our results indicate that pterostilbene can be suggested as a promising chemopreventive agent and the cytotoxicity promoted by this compound in tumor cells possibly requires p53 function.