p53 Aggregation in cancer: Molecular mechanisms, functional disruptions, and targeted therapies

The concept of tumors as prion-like diseases similar to neurodegenerative disorders has gained attraction in recent years. p53, the most well-known tumor suppressor, has been extensively studied for its expression, mutations, and functions in various cancers. Recent findings reveal that p53 undergoes prion-like aggregation in tumors, leading to pathological amyloid fibril formation, functional alterations, and tumor progression. The mechanisms of p53 aggregation involve mutations, structural domains, isoforms, and external factors such as Zn²⁺ concentrations, pH, temperature, and chaperone abnormalities. While the role of p53 aggregation in tumors is increasingly recognized, controversies remain regarding its precise pathogenic mechanisms. This chapter reviews the structural features of p53 amyloid fibrils, its aggregation characteristics and effects, and the molecular mechanisms driving this phenomenon. Additionally, this chapter summarizes current therapeutic approaches targeting p53 aggregation and prion-like behavior, including small molecules and peptides designed to inhibit aggregation and restore p53's tumor suppressive function. By illuminating these aspects, this chapter aims to deepen our comprehension of how p53 aggregation disrupts its physiological functions. It also highlights the potential of targeting these aggregates as a novel therapeutic strategy in cancer treatment.