p53 amyloid aggregation in cancer: function, mechanism, and therapy

Abstract

Similar to neurodegenerative diseases, the concept that tumors are prion like diseases has been proposed in recent years. p53, the most well-known tumor suppressor, has been extensively studied for its expression, mutation, and function in various tumors. Currently, an interesting phenomenon of p53 prion-like aggregation has been found in several tumors, and studies have found that its pathological aggregation may lead to functional alterations and ultimately affect tumor progression. It has been demonstrated that the mechanism of p53 aggregation involves its mutation, domains, isoform, etc. In addition to p53 itself, some other factors, including Zn²⁺ concentration, pH, temperature and chaperone abnormalities, can also contribute to p53 aggregation. Although there are some studies about the mechanism and role of p53 aggregation and amyloidosis in tumors, there still exist some controversies. In this paper, we review the mechanism of p53 amyloid fibril structure and discuss the characteristics and effects of p53 amyloid aggregation, as well as the pathogenic mechanism leading to the occurrence of aggregation in tumors. Finally, we summarize the various inhibitors targeting p53 aggregation and prion-like behavior. In conclusion, a comprehensive understanding of p53 aggregation can expand our understanding of the causes leading its loss of physiological function and that targeting p53 aggregation might be a promising therapeutic strategy for tumor therapy.

Keywords: Aggregation; Amyloid; Cancer; Mechanism; p53.

Fig. 1

Illustration of p53 aggregation and the regulating factors. The scheme shows a potential route of aggregation, from the properly folded state, native state, to misfolded, aggregated forms of p53, including oligomers and amyloid fibrils. The main factors regulating p53 aggregation. (1) Some structural mutations, domains, and isoforms; (2) Chaperones, cochaperones, and some fiber stabilization factors are integrated into p53 amyloid aggregates, and abnormalities occur when they help p53-fold. (3) The protein state depends on the thermodynamic and kinetic factors in different environments. When the solution environment, such as Zn²⁺ concentration, pH, temperature, and pressure is changed, p53 may aggregate. (4) RNA molecules also modulate of p53 aggregation and seeding

Fig. 2

The roles of p53 aggregation in tumor progression. (1) In normal cells, wild-type p53 is functional at the nucleolus and can regulate the cell cycle and preserve cell integrity. (2) In cells expressing an aggregation-prone mutant p53, mutant p53 can interact with homologs p63/p73 or Hsp70/90. p53 will be inactivated due to genomic or cancer cell-specific mutation events. (3) Aggregated p53 may interact with different proteins, such as p63/p73 and heat shock proteins. p53 aggregation might lead to the following three kinds of effects. (4) Loss-of function [LoF]: Losing wild-type activity, p53 is no longer active in the nucleolus. (5) Gain-of-function [GoF]: Acquire oncogenic activity without disrupting the activity of wild-type p53. (6) Dominant-negative [DN]: Inhibit the wild-type p53 protein via a dominant-negative effect and display oncogenic activity (GoF) or no other activity (LoF)

Fig. 3

Different domains, mutants, and isoforms of p53 related to aggregation. Top: The sites of aggregation-related mutations are indicated by the corresponding residues. The bars above show the relative frequencies of missense mutations at the residues according to version R20 (July 2019) of the International Agency for Research on Cancer (IARC) tumor suppressor protein p53 (TP53) Database (http://www-p53.iarc.fr/). Middle: The frames show the different domains of p53 related to aggregation; the blue arrow shows the aggregation-nucleating segment. Bottom: The arrows indicate the start point (N-terminus) of the isoforms; the terminal arrows represent the C-terminal isoform variants. Transactivation domain I (TAD I); transactivation domain II (TAD II); proline rich domain (PRD); DNA-binding domain (DBD); oligomerization domain (OD); C-terminal domain (CTD)

Fig. 4

Strategies to recover p53 function in cancer therapy. (1) L^I, ADH-6, ReACp53 can block p53 aggregation and prion-like behavior. (2) CDB3, CP31398 can stabilize p53 and restore the normal functionality. (3) Nutlins, MI series can interfere with the binding of p53-MDM2 and recover the function of p53. (4) Transfecting functional p53 via viruses to recover p53 function