Reactivation of P53 Antiproliferative and Pro-Apoptotic Pathways by Resveratrol in Mutant P53 Cancer Cell Lines

Cancer is the second leading cause of death worldwide. Mutations in the TP53 gene lead to a loss of tumor suppressor function and an oncogenic gain of function for the protein, resulting in a more invasive, metastatic, and chemoresistant phenotype. Diverse structural studies have demonstrated that mutant p53 core domain unfolding is not irreversible. Thus, reactivation toward its wild-type-like conformation or inactivation of its mutant p53 capacities may restore the expression of genes in its tumor suppressor pathways, resulting in enhanced responses to current therapies. Resveratrol (3,4',5-trihydroxy-trans-stilbene) is a phytoalexin naturally found in more than 70 plant species that has widely proven antiproliferative and pro-apoptotic properties, as well as a capacity to reverse multidrug resistance in various cancer types. Interestingly, it has recently been demonstrated that resveratrol directly interacts with the p53 core domain and reduces mutant p53 aberrant aggregation. In this context, our study aims to elucidate whether resveratrol may induce antiproliferative and pro-apoptotic pathways regardless of a mutant background. We observed that resveratrol has an antiproliferative effect in cancer cells, independent of p53 status, and leads to apoptosis after 48 h of treatment. Resveratrol also induces the expression of p53 tumor suppressor target genes, which are involved in cell cycle arrest and apoptosis. Even though the previous effects are more significant in cells expressing wild-type p53, resveratrol drastically sensitizes all cancer cell lines, regardless of p53 status, to cisplatin treatment, making it a promising enhancer compound to overcome chemoresistance associated with p53.