[PDF][PDF] A designed inhibitor of p53 aggregation rescues p53 tumor suppression in ovarian carcinomas

A Soragni, DM Janzen, LM Johnson, AG Lindgren… - Cancer cell, 2016 - cell.com
A Soragni, DM Janzen, LM Johnson, AG Lindgren, ATQ Nguyen, E Tiourin, AB Soriaga, J Lu…
Cancer cell, 2016cell.com
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 …
Summary
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.
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