title: A Designed Inhibitor of p53 Aggregation Rescues p53 Tumor Suppression in Ovarian Carcinomas.
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.
authors.affiliation: Departments of Biological Chemistry and Chemistry and Biochemistry, UCLA-DOE Institute, HHMI, 611 South Charles E. Young Drive, Los Angeles, CA 90095-1570, USA.
authors.forename: Alice
authors.initials: A
authors.lastname: Soragni
authors.affiliation: Department of Obstetrics and Gynecology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Deanna M
authors.initials: DM
authors.lastname: Janzen
authors.affiliation: Departments of Biological Chemistry and Chemistry and Biochemistry, UCLA-DOE Institute, HHMI, 611 South Charles E. Young Drive, Los Angeles, CA 90095-1570, USA.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Johnson
authors.affiliation: Department of Obstetrics and Gynecology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Anne G
authors.initials: AG
authors.lastname: Lindgren
authors.affiliation: Departments of Biological Chemistry and Chemistry and Biochemistry, UCLA-DOE Institute, HHMI, 611 South Charles E. Young Drive, Los Angeles, CA 90095-1570, USA.
authors.forename: Anh
authors.initials: A
authors.lastname: Thai-Quynh Nguyen
authors.affiliation: Department of Obstetrics and Gynecology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Tiourin
authors.affiliation: Departments of Biological Chemistry and Chemistry and Biochemistry, UCLA-DOE Institute, HHMI, 611 South Charles E. Young Drive, Los Angeles, CA 90095-1570, USA.
authors.forename: Angela B
authors.initials: AB
authors.lastname: Soriaga
authors.affiliation: Molecular, Cell and Developmental Biology, University of California Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Lu
authors.affiliation: Departments of Biological Chemistry and Chemistry and Biochemistry, UCLA-DOE Institute, HHMI, 611 South Charles E. Young Drive, Los Angeles, CA 90095-1570, USA.
authors.forename: Lin
authors.initials: L
authors.lastname: Jiang
authors.affiliation: Pasarow Mass Spectrometry Laboratory, Semel Institute, 405 Hilgard Avenue, Los Angeles, CA 90095, USA.
authors.forename: Kym F
authors.initials: KF
authors.lastname: Faull
authors.affiliation: Molecular, Cell and Developmental Biology, University of California Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Matteo
authors.initials: M
authors.lastname: Pellegrini
authors.affiliation: 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.
authors.forename: Sanaz
authors.initials: S
authors.lastname: Memarzadeh
authors.affiliation: 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.
authors.forename: David S
authors.initials: DS
authors.lastname: Eisenberg
mesh_terms: D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation / Q000235:genetics*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008822:Mice, Transgenic; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D016159:Tumor Suppressor Protein p53