Targeting mutant p53 stabilization for cancer therapy

Abstract

Over 50% cancer bears TP53 mutation, the highly stabilized mutant p53 protein drives the tumorigenesis and progression. Mutation of p53 not only cause loss-of-function and dominant-negative effects (DNE), but also results in the abnormal stability by the regulation of the ubiquitin-proteasome system and molecular chaperones that promote tumorigenesis through gain-of-function effects. The accumulation of mutant p53 is mainly regulated by molecular chaperones, including Hsp40, Hsp70, Hsp90 and other biomolecules such as TRIM21, BAG2 and Stat3. In addition, mutant p53 forms prion-like aggregates or complexes with other protein molecules and result in the accumulation of mutant p53 in tumor cells. Depleting mutant p53 has become one of the strategies to target mutant p53. This review will focus on the mechanism of mutant p53 stabilization and discuss how the strategies to manipulate these interconnected processes for cancer therapy.

Knockdown of TFAP2E results in rapid G2/M transition in oral squamous cell carcinoma cells

“…Predictably, depletion of TP53 suppressed, rather than increased, the proliferation rate of both cell lines, indicating that downregulation of the TP53 protein could not be responsible for the increased proliferation rate of TFAP2E-knockdown cells. Nevertheless, as the stability of mutant TP53 is regulated by multiple pathways ( 33 ), the observations presented in Fig. S4B suggest the involvement of TFAP2E in one of these pathways.…”

Mechanistic Aspects of Biphenyl Urea-Based Analogues in Triple-Negative Breast Cancer Cell Lines

“…We observed that heat shock proteins, such as HSP40 and HSP90, that act as chaperones for p53 had been downregulated in treated cells. It has been shown that reduction in HSP90 releases mutated p53 and reactivates endogenous MDM2 for p53 degradation . At the same time, we observed no changes in expression levels of MDMD2, which are responsible for the degradation of p53.…”

Understanding the prion-like behavior of mutant p53 proteins in triple-negative breast cancer pathogenesis: The current therapeutic strategies and future directions

“…In this regard, another study has been conducted on the effects of DnaJ Heat Shock Protein Family (DNAJA1) [also known as HSP40] molecule on the cells containing the mutant p53 [ 112 ]. This molecule, with its chaperone role, protects the mutant misfolded p53 against proteasome degradation [ 113 ]. Moreover, previous studies have proven that the degradation of the mutated p53 suppresses the tumor.…”