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

Rangel, Luciana P. ; Ferretti, Giulia D.S. ; Costa, Caroline L. ; Andrade, Sarah M.M.V. ; Carvalho, Renato S. ; Costa, Danielly C.F. ; Silva, Jerson L.

The Journal of biological chemistry, 2019-03, Vol.294 (10), p.3670-3682 [Periódico revisado por pares]

United States: Elsevier Inc

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Título:
p53 reactivation with induction of massive apoptosis-1 (PRIMA-1) inhibits amyloid aggregation of mutant p53 in cancer cells
Autor: Rangel, Luciana P. ; Ferretti, Giulia D.S. ; Costa, Caroline L. ; Andrade, Sarah M.M.V. ; Carvalho, Renato S. ; Costa, Danielly C.F. ; Silva, Jerson L.
Assuntos: amyloid ; Amyloid - chemistry ; anticancer drug ; Aza Compounds - chemistry ; Bridged Bicyclo Compounds, Heterocyclic - chemistry ; Cell Line, Tumor ; Humans ; Mutant Proteins - genetics ; Mutant Proteins - metabolism ; Mutation ; p53 ; Protein Aggregates ; protein aggregation ; protein misfolding ; Protein Multimerization ; Protein Structure and Folding ; Protein Structure, Secondary ; Quinuclidines - chemistry ; Quinuclidines - metabolism ; Tumor Suppressor Protein p53 - genetics ; Tumor Suppressor Protein p53 - metabolism
É parte de: The Journal of biological chemistry, 2019-03, Vol.294 (10), p.3670-3682
Notas: ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
Both authors contributed equally to this work.
Edited by Paul E. Fraser
Descrição: 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.
Editor: United States: Elsevier Inc
Idioma: Inglês

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

Rangel, Luciana P. ; Ferretti, Giulia D.S. ; Costa, Caroline L. ; Andrade, Sarah M.M.V. ; Carvalho, Renato S. ; Costa, Danielly C.F. ; Silva, Jerson L.

United States: Elsevier Inc

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