PRIMA-1 inhibits Y220C p53 amyloid aggregation and synergizes with cisplatin in hepatocellular carcinoma

Frontiers in Molecular Biosciences

Molecular Biosciences

Thibaut Barnoud¹  Luciana P. Rangel²  Yraima Cordeiro²  Mariana M. Paz²  Jerson L. Silva³  Mafalda M. C. Martins-Dinis³  Giulia D. S. Ferretti⁴  Beatriz I. S. Ferreira⁵  Otacilio C. Moreira⁵  Amanda Faier-Pereira⁵ 

[1] Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC, United States;Faculty of Pharmacy, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil;Institute of Medical Biochemistry Leopoldo de Meis, National Institute of Science and Technology for Structural Biology and Bioimaging, National Center of Nuclear Magnetic Resonance Jiri Jonas, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil;Institute of Medical Biochemistry Leopoldo de Meis, National Institute of Science and Technology for Structural Biology and Bioimaging, National Center of Nuclear Magnetic Resonance Jiri Jonas, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil;Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC, United States;Real Time PCR Platform RPT09A, Laboratory of Molecular Virology and Parasitology, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil;

关键词: p53;    amyloid aggregation;    PRIMA-1;    hepatocellular carcinoma;    cisplatin;   

DOI  :  10.3389/fmolb.2023.1165132

 received in 2023-02-13, accepted in 2023-03-22,  发布年份 2023

来源: Frontiers

【 摘 要 】

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide. Although many therapeutic options are available, several factors, including the presence of p53 mutations, impact tumor development and therapeutic resistance. TP53 is the second most frequently mutated gene in HCC, comprising more than 30% of cases. Mutations in p53 result in the formation of amyloid aggregates that promote tumor progression. The use of PRIMA-1, a small molecule capable of restoring p53, is a therapeutic strategy to pharmacologically target the amyloid state mutant p53. In this study, we characterize an HCC mutant p53 model for the study of p53 amyloid aggregation in HCC cell lines, from in silico analysis of p53 mutants to a 3D-cell culture model and demonstrate the unprecedented inhibition of Y220C mutant p53 aggregation by PRIMA-1. In addition, our data show beneficial effects of PRIMA-1 in several “gain of function” properties of mutant-p53 cancer cells, including migration, adhesion, proliferation, and drug resistance. We also demonstrate that the combination of PRIMA-1 and cisplatin is a promising approach for HCC therapy. Taken together, our data support the premise that targeting the amyloid-state of mutant p53 may be an attractive therapeutic approach for HCC, and highlight PRIMA-1 as a new candidate for combination therapy with cisplatin.

【 授权许可】

Unknown   
Copyright © 2023 Paz, Ferretti, Martins-Dinis, Ferreira, Faier-Pereira, Barnoud, Moreira, Silva, Cordeiro and Rangel.