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Cancer Cell. 2016 Jan 11;29(1):90-103. doi: 10.1016/j.ccell.2015.12.002. Epub 2015 Dec 31.

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

Author information

1
Departments of Biological Chemistry and Chemistry and Biochemistry, UCLA-DOE Institute, HHMI, 611 South Charles E. Young Drive, Los Angeles, CA 90095-1570, USA.
2
Department of Obstetrics and Gynecology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA.
3
Molecular, Cell and Developmental Biology, University of California Los Angeles, Los Angeles, CA 90095, USA.
4
Pasarow Mass Spectrometry Laboratory, Semel Institute, 405 Hilgard Avenue, Los Angeles, CA 90095, USA.
5
Department of Obstetrics and Gynecology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California Los Angles, Los Angeles, CA 90095, USA; The VA Greater Los Angeles Health Care System, Los Angeles, CA 90073, USA. Electronic address: smemarzadeh@mednet.ucla.edu.
6
Departments of Biological Chemistry and Chemistry and Biochemistry, UCLA-DOE Institute, HHMI, 611 South Charles E. Young Drive, Los Angeles, CA 90095-1570, USA. Electronic address: david@mbi.ucla.edu.

Abstract

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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PMID:
26748848
PMCID:
PMC4733364
DOI:
10.1016/j.ccell.2015.12.002
[Indexed for MEDLINE]
Free PMC Article
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