Unraveling the unique amyloid-like aggregation behavior of the tumor suppressor p53 mutants in human cancers

Abstract

Missense mutations in the tumor suppressor p53 significantly disrupt its native structure and functions, playing a pivotal role in human cancer pathogenesis. Oncogenic mutant p53 (mutp53) not only loses its tumor-suppressive capabilities but also acquires oncogenic functions, driving cancer progression, metastasis, and chemoresistance. Despite extensive research on mutp53, the role of missense mutations in triggering amyloid-like aggregation of p53 remains an underexplored and fascinating area of study.

To date, over 50 proteins are known to form amyloid-like aggregates due to abnormal folding, resulting in insoluble protein fibrils that contribute to various protein misfolding diseases, including cancer. However, the precise mechanisms by which aggregated proteins induce cancer remain inadequately understood. Notably, certain p53 mutations promote its aggregation, which has emerged as a critical factor in protein aggregation-induced oncogenesis.

This review delves into the mechanisms underpinning mutp53 aggregation, emphasizing unique properties such as coaggregation, bio-isolation, prion-like cell-to-cell transmission, and chemoresistance promotion. Leveraging diverse in-silico, biophysical, and biochemical approaches, we comprehensively analyzed the aggregating potential of 26 mutp53 variants among 1297 missense mutations identified in human cancers. These findings shed light on the multifaceted roles of mutp53 aggregates in oncogenesis and tumor progression.

Lastly, we present an integrative exploration of emerging therapeutic strategies designed to disaggregate mutp53 aggregates, offering promising directions for targeted cancer therapy. By addressing this enigmatic aspect of mutp53 biology, our review advances the understanding of protein aggregation in cancer and identifies avenues for innovative therapeutic interventions.