A Designed Inhibitor of p53 Aggregation Rescues p53 Tumor Suppression in Ovarian Carcinomas

Publication date: Available online 31 December 2015
Source:Cancer Cell
Author(s): Alice Soragni, Deanna M. Janzen, Lisa M. Johnson, Anne G. Lindgren, Anh Thai-Quynh Nguyen, Ekaterina Tiourin, Angela B. Soriaga, Jing Lu, Lin Jiang, Kym F. Faull, Matteo Pellegrini, Sanaz Memarzadeh, David S. Eisenberg
Half of all human cancers lose p53 function by missense mutations, with an unknown fraction of these containing p53 in a self-aggregated amyloid-like state. Here we show that a cell-penetrating peptide, ReACp53, designed to inhibit p53 amyloid formation, rescues p53 function in cancer cell lines and in organoids derived from high-grade serous ovarian carcinomas (HGSOC), an aggressive cancer characterized by ubiquitous p53 mutations. Rescued p53 behaves similarly to its wild-type counterpart in regulating target genes, reducing cell proliferation and increasing cell death. Intraperitoneal administration decreases tumor proliferation and shrinks xenografts in vivo. Our data show the effectiveness of targeting a specific aggregation defect of p53 and its potential applicability to HGSOCs.

Graphical abstract

Teaser

Using p53-mutant, high-grade, serous ovarian carcinoma as model systems, Soragni et al. show that a cell-penetrating peptide designed to inhibit p53 amyloid formation rescues p53 functions and reduces in vivo xenograft growth and metastasis.


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