p53 reactivation with induction of massive apoptosis-1 (PRIMA-1) inhibits amyloid aggregation of mutant p53 in cancer cells.

Abstract

p53 mutants can form amyloid-like structures that accumulate in cells. p53 reactivation with induction of massive apoptosis-1 (PRIMA-1) and its primary active metabolite, 2-methylene-3-quinuclidinone (MQ), can restore unfolded p53 mutants to a native conformation that induces apoptosis and activates several p53 target genes. However, whether PRIMA-1 can clear p53 aggregates is unclear. In this study, we investigated whether PRIMA-1 can restore aggregated mutant p53 to a native form. We observed that the p53 mutant protein is more sensitive to both PRIMA-1 and MQ aggregation inhibition than WT p53. The results of anti-amyloid oligomer antibody assays revealed that PRIMA-1 reverses mutant p53 aggregate accumulation in cancer cells. Size-exclusion chromatography of the lysates from mutant p53-containing breast cancer and ovarian cell lines confirmed that PRIMA-1 substantially decreases p53 aggregates. We also show that MDA-MB-231 cell lysates can "seed" aggregation of the central core domain of recombinant WT p53, corroborating the prion-like behavior of mutant p53. We also noted that this aggregation effect was inhibited by MQ and PRIMA-1. This study provides the first demonstration that PRIMA-1 can rescue amyloid-state p53 mutants, a strategy that could be further explored as a cancer treatment.

• Authors: Luciana P Rangel, Giulia D S Ferretti, Caroline L Costa, Sarah M M V Andrade, Renato S Carvalho, Danielly C F Costa, Jerson L Silva
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 294 Issue 10 Pg. 3670-3682 (03 08 2019) ISSN: 1083-351X [Electronic] United States
• PMID: 30602570 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2019 Rangel et al.

Chemical References

• Amyloid
• Aza Compounds
• Bridged Bicyclo Compounds, Heterocyclic
• Mutant Proteins
• Protein Aggregates
• Quinuclidines
• Tumor Suppressor Protein p53
• 2,2-bis(hydroxymethyl)-1-azabicyclo(2,2,2,)octan-3-one

Topics

• Amyloid (chemistry)
• Aza Compounds (chemistry)
• Bridged Bicyclo Compounds, Heterocyclic (chemistry)
• Cell Line, Tumor
• Humans
• Mutant Proteins (genetics, metabolism)
• Mutation
• Protein Aggregates
• Protein Multimerization
• Protein Structure, Secondary
• Quinuclidines (chemistry, metabolism)
• Tumor Suppressor Protein p53 (genetics, metabolism)