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

Soragni, Alice; Janzen, Deanna M.; Johnson, Lisa M.; Lindgren, Anne G.; Thai-Quynh Nguyen, Anh; Tiourin, Ekaterina; Soriaga, Angela B.; Lu, Jing; Jiang, Lin; Faull, Kym F.; Pellegrini, Matteo; Memarzadeh, Sanaz; Eisenberg, David S.

doi:10.1016/j.ccell.2015.12.002

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

Journal Article · Thu Dec 31 00:00:00 EST 2015 · Cancer Cell

DOI:https://doi.org/10.1016/j.ccell.2015.12.002· OSTI ID:1236262

Soragni, Alice ^[1]; Janzen, Deanna M. ^[2]; Johnson, Lisa M. ^[1]; Lindgren, Anne G. ^[2]; Thai-Quynh Nguyen, Anh ^[1]; Tiourin, Ekaterina ^[2]; Soriaga, Angela B. ^[1]; Lu, Jing ^[2]; Jiang, Lin ^[1]; Faull, Kym F. ^[3]; Pellegrini, Matteo ^[2]; Memarzadeh, Sanaz ^[4]; Eisenberg, David S. ^[1]

UCLA-DOE Inst., Los Angeles, CA (United States)
Univ. of California, Los Angeles, CA (United States)
Semel Inst., Los Angeles, CA (United States)
Univ. of California, Los Angeles, CA (United States); The VA Greater Los Angeles Health Care System, Los Angeles, CA (United States)

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. In this paper 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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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: USDOE Office of Science (SC); National Institutes of Health (NIH); Pardee Foundation; American Cancer Society; National Science Foundation (NSF); Jonsson Cancer Center Foundation; Lynne Cohen Foundation; Phase One Foundation; Ovarian Cancer Circle Inspired by Robin Babbini; Leath L. and Marcia L. Millen Family Fund; G.O. Discovery Laboratory Foundation; Howard Hughes Medical Institute (HHMI); US Department of Veterans Affairs (VA)

Grant/Contract Number:: 1S10RR023718-01A2; AG-029430; R01CA183877; UL1TR000124; RSG-14-217-01-TBG; MCB 0958111; 1 K12 BX 001305-01

OSTI ID:: 1236262

Journal Information:: Cancer Cell, Vol. 29, Issue 1; ISSN 1535-6108

Publisher:: ElsevierCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Cited by: 229 works

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