p53-REACT · Dynamics of p53 mutant reactivation and the anti-carcinogenic action of engineered resveratrol analogues

Dynamics of p53 mutant reactivation and the anti-carcinogenic action of engineered resveratrol analogues

The p53-REACT project (“named after p53 REACTivation”) tackled a critical challenge in cancer therapy by targeting the mutated p53 protein, implicated in over half of all cancer cases worldwide. While chemotherapy and radiotherapy are common treatments, they often fail in many patients, highlighting the need to understand tumor resistance. Known as the “guardian of the genome,” p53 plays a crucial role in protecting DNA from cancer-inducing mutations. When p53 loses its function, it can form harmful aggregates that contribute to tumor growth and treatment resistance. These p53 clusters share traits with prion diseases and are increasingly linked to cancer progression The project aimed to develop strategies to inhibit the aggregation of p53. By studying p53’s structure and function, the focus was on restoring its normal activity—a process called reactivation—to advance cancer treatments. Some mutated p53 forms interact with healthy p53 proteins, blocking their function, while others acquire entirely new harmful properties Addressing these diverse dysfunctions is challenging, particularly due to the difficulty of breaking down mature aggregates. To address these complexities, p53-REACT has identified small molecules, particularly modified structures of resveratrol, an antioxidant polyphenol found in grapes and red wine, that shows potential to interact with p53 and inhibit cancer development. Pre-selected resveratrol analogues were investigated for their ability to enhance the stability of p53 and restore its normal function. A key aspect of the project was the biosynthesis of resveratrol analogues. Using metabolic engineering, a platform was developed to engineer bacterial strains capable of cyclically producing these variants. The obtained cells served as factories for producing and diversifying target chemicals. In a final controlled study, structural biology and thermodynamics were applied to analyze the interactions between the validated resveratrol analogues and p53 family proteins. The modified chemical groups in resveratrol acted as conformational effectors, influencing p53 by altering the energy landscape and aggregation process based on the size, position, and oxidation properties of the substituents. The research provided a high-resolution understanding of how resveratrol analogues impact p53 in vitro, offering promising tools to sustainably restore p53 function and combat cancer treatment resistance. This advancement will enable more effective cancer diagnosis and therapeutics, enhancing the visibility of research outcomes to society.

Data: CORDIS, © European Union