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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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE74550 | GEO | 2016/01/04

SECONDARY ACCESSION(S): PRJNA300686

REPOSITORIES: GEO

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A designed inhibitor of p53 aggregation rescues p53 tumor-suppression in ovarian carcinomas

Project description: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. Vehicle vs. ReACp53 treatment in 4 different samples: 2 cell lines (MCF7 w/ WT p53 as negative control and OVCAR3 w/ R248Q p53) and 2 clinical specimens (primary cells from patient #8 w/ WT p53 as negative control and primary cells from patient #1 w/ R248Q p53)

2016-01-04 | E-GEOD-74550 | biostudies-arrayexpress

Protein mimetic amyloid inhibitor potently abrogates cancer-associated mutant p53 aggregation and restores tumor suppressor function

Project description:Transcriptome analysis of protein mimetic amyloid inhibitor that potently abrogates cancer-associated mutant p53 aggregation and restores tumor suppressor function

2020-11-23 | GSE161952 | GEO

p53 amyloid formation induced cellular transformation and tumor formation in xenograft model

Project description:p53 mutation and its subsequent loss of function along with gain of oncogenic functions is associated with cancer. However, the exact mechanism of how altered p53 acts as an oncogene is not clear yet. Recently, it was suggested that p53 aggregation and amyloid formation leads to both loss of tumor suppressive function and gain of oncogenic functions in cells. In this study, we directly demonstrate that wild-type p53 amyloid formation imparts oncogenic properties to normal cells. Cells with p53 amyloid aggregates show enhanced survival, apoptotic resistance with increased proliferation and migration rate. We further establish the tumorigenic potential of p53 amyloid containing cells in a mice xenograft model. Furthermore, these tumors tested positive for p53 amyloid aggregates. Comprehensive gene-expression analysis suggests that p53 amyloid formation triggers aberrant expression of pro-oncogenes while downregulating the tumor suppressor associated genes. Interestingly, disaggregating p53 rescues the cellular transformation and also inhibits tumor development in mice. We propose that wild-type p53 amyloid formation can potentially contribute to initiation of tumor development.

2020-05-14 | GSE150522 | GEO

p53 amyloid induced cellular transformation and tumor formation in the mouse xenograft model

Project description:p53 amyloid formation is predicted to be involved in cancer initiation, but the direct evidence of how altered p53 acts as an oncogene is lacking. Cells with p53 amyloids show enhanced survival, apoptotic resistance with increased proliferation and migration rates. Proteomic profiling of cells containing p53 aggregates suggests that p53 amyloid formation triggers aberrant expression of pro-oncogenes while downregulating the tumor-suppressive genes. We propose that wild-type p53 amyloid formation can potentially contribute to the initiation of tumor development.

2022-07-16 | PXD019498 | Pride

Protein mimetic amyloid inhibitor potently abrogates cancer-associated mutant p53 aggregation and restores tumor suppressor function

Project description:It is a TMT10Plex proteomics dataset used for relative protein and phosphoprotein quantification in the manuscript entitled "Protein mimetic amyloid inhibitor potently abrogates cancer-associated mutant p53 aggregation and restores tumor suppressor function". It contains both non-phosphorylated (used for identification and quantification of total proteomes) and phospho enriched (used for identification and quantification of phosphoproteins) dataset.

2020-12-05 | MSV000086563 | MassIVE

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

Project description: Not available

| S-EPMC4733364 | biostudies-literature

A p53 super-tumor suppressor reveals a tumor suppressive p53-Ptpn14-Yap axis in pancreatic cancer

Project description:The p53 transcription factor is a critical barrier to pancreatic cancer progression. To unravel mechanisms of p53-mediated tumor suppression, we analyzed pancreatic cancer predisposition in mice expressing p53 transactivation domain (TAD) mutants. Surprisingly, we observed that p53 TAD2 mutant behaves as a “super-tumor suppressor”, with an enhanced capacity to suppress pancreatic cancer and to activate a subset of novel p53 target genes. One such gene, Ptpn14, is a direct p53-inducible gene encoding a negative regulator of the Yap oncoprotein. To determine the effects of p53 deficiency on Yap target gene expression in pre-malignant mouse pancreatic intraepithelial neoplasia (PanIN) lesions, we sorted the CD133-positive ductal epithelial cells that make up the PanINs and used these cells for RNA-sequencing analysis. This analysis revealed that a Yap signature is induced upon p53 deficiency, suggesting that p53 loss promotes the induction of a Yap transcriptional program.

2017-10-26 | GSE94566 | GEO

The effect of Mtb aggregation on monocyte-derived macrophage transcription profiles

Project description:Mycobacterium tuberculosis (Mtb) bacilli readily aggregate. We previously reported that Mtb aggregates lead to phagocyte death and subsequent efficient replication in the dead infected cells. Here we examined the transcriptional response of human monocyte derived macrophages to phagocytosis of aggregated Mtb relative to phagocytosis of non-aggregated single or multiple bacilli. Infection with aggregated Mtb led to an early upregulation of pro-inflammatory associated genes and enhanced TNF-alpha signaling via the NFkappaB pathway. These pathways were significantly more highly upregulated relative to infection with single or multiple non-aggregated bacilli per cell.

2021-04-30 | GSE173560 | GEO

Identification of temperature-sensitive (TS) p53 mutations and potassium antimony tartrate (PAT)-treatable p53 mutations in mammalian U937 (free of endogenous p53) cells using a systematic p53 mutation library

Project description:To identified TS p53 mutations and PAT-treatable p53 mutations in mammalian U937 cells.

2022-05-02 | GSE174348 | GEO

Mutant p53 interactome study with IP-MS

Project description:Inactivating TP53 mutations lead to a loss of function of p53, but can also often result in oncogenic gain-of-function (GOF) of mutant p53 (mutp53) proteins which promote tumor development and progression. The GOF activities of TP53 mutations are well documented, but the mechanisms involved remain poorly understood. Here, we study the mutp53 interactome with IP-MS.

2023-11-27 | PXD047094 | Pride

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