Restoration of Wild-Type Activity to Mutant p53 in Prostate Cancer: A Novel Therapeutic Approach

2008 ◽  
Author(s):  
James J. Manfredi
Keyword(s):  
Prostate Cancer ◽  
Therapeutic Approach ◽  
Mutant P53 ◽  
Wild Type ◽  
Type Activity ◽  
Novel Therapeutic

Modulation of β-catenin-mediated TCF-signalling in prostate cancer cell lines by wild-type and mutant p53

The Prostate ◽  
2007 ◽  
Vol 67 (16) ◽  
pp. 1751-1760 ◽  
Author(s):  
Alexandra Prowald ◽  
Marcus V. Cronauer ◽  
Christoph von Klot ◽  
Tyark Eilers ◽  
Ludwig Rinnab ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Lines ◽  
Cancer Cell ◽  
Prostate Cancer Cell ◽  
Cancer Cell Lines ◽  
Mutant P53 ◽  
Wild Type ◽  
Prostate Cancer Cell Lines

scholarly journals Effect of Piceatannol on Cell Cycle Progression in Prostate Cancer Cells (P05-005-19)

2019 ◽  
Vol 3 (Supplement_1) ◽  
Author(s):  
Larissa Kido ◽  
Eun-Ryeong Hahm ◽  
Valeria Cagnon ◽  
Mário Maróstica ◽  
Shivendra Singh
Keyword(s):  
Prostate Cancer ◽  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Cell Lines ◽  
Cell Cycle Progression ◽  
Cell Cycle Distribution ◽  
Mutant P53 ◽  
Wild Type ◽  
Cycle Progression ◽  
Cycle Arrest

Abstract Objectives Piceatannol (PIC) is a polyphenolic and resveratrol analog that is found in many vegetables consumed by humans. Like resveratrol, PIC has beneficial effects on health due to its anti-inflammatory, anti-oxidative and anti-proliferative features. However, the molecular targets of PIC in prostate cancer (PCa), which is the second most common cancer in men worldwide, are still poorly understood. Preventing cancer through dietary sources is a promising strategy to control diseases. Therefore, the aim of present study was to investigate the molecular mechanistic of actions of PIC in PCa cell lines with different genetic background common to human prostate cancer. Methods Human PCa cell lines (PC-3, 22Rv1, LNCaP, and VCaP) were treated with different doses of PIC (5–40 µM) and used for cell viability assay, measurement of total free fatty acids (FFA) and lactate, and cell cycle distribution. Results PIC treatment dose- and time-dependently reduced viability in PC-3 (androgen-independent, PTEN null, p53 null) and VCaP cells (androgen-responsive, wild-type PTEN, mutant p53). Because metabolic alterations, such as increased glucose and lipid metabolism are implicated in pathogenesis of in PCa, we tested if PIC could affect these pathways. Results from lactate and total free fatty acid assays in VCaP, 22Rv1 (castration-resistant, wild-type PTEN, mutant p53), and LNCaP (androgen-responsive, PTEN null, wild-type p53) revealed no effect of PIC on these metabolisms. However, PIC treatment delayed cell cycle progression in G0/G1 phase concomitant with the induction of apoptosis in both LNCaP and 22Rv1 cells, suggesting that growth inhibitory effect of PIC in PCa is associated with cell cycle arrest and apoptotic cell death at least LNCaP and 22Rv1 cells. Conclusions While PIC treatment does not alter lipid or glucose metabolism, cell cycle arrest and apoptosis induction are likely important in anti-cancer effects of PIC. Funding Sources São Paulo Research Foundation (2018/09793-7).

Abstract B052: Leveraging the metabolic stress of polyamine biosynthesis in prostate cancer towards a novel therapeutic approach

2018 ◽  
Author(s):  
Hayley C. Affronti ◽  
Anthony J. Pellerite ◽  
Aryn Rowsam ◽  
Spencer R. Rosario ◽  
Robert A. Casero ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Therapeutic Approach ◽  
Metabolic Stress ◽  
Polyamine Biosynthesis ◽  
Novel Therapeutic

Single chain antibody against the common epitope of mutant p53 restores wild-type activity to mutant p53 protein

FEBS Letters ◽  
2005 ◽  
Vol 579 (25) ◽  
pp. 5609-5615 ◽  
Author(s):  
Sara Orgad ◽  
Naomi Goldfinger ◽  
Gerald Cohen ◽  
Varda Rotter ◽  
Beka Solomon
Keyword(s):  
P53 Protein ◽  
Mutant P53 ◽  
Wild Type ◽  
Single Chain ◽  
Single Chain Antibody ◽  
Type Activity ◽  
The Common

scholarly journals Mutant p53 tumor suppressor alleles release ras-induced cell cycle growth arrest.

1991 ◽  
Vol 11 (3) ◽  
pp. 1344-1352 ◽  
Author(s):  
G G Hicks ◽  
S E Egan ◽  
A H Greenberg ◽  
M Mowat
Keyword(s):  
Cell Cycle ◽  
Tumor Suppressor ◽  
Growth Regulation ◽  
Growth Arrest ◽  
Mutant P53 ◽  
Wild Type ◽  
Type Activity ◽  
Wild Type P53 ◽  
Negative Growth ◽  
P53 Genes

Overexpression of an activated ras gene in the rat embryo fibroblast line REF52 results in growth arrest at either the G1/S or G2/M boundary of the cell cycle. Both the DNA tumor virus proteins simian virus 40 large T antigen and adenovirus 5 E1a are able to rescue ras induced lethality and cooperate with ras to fully transform REF52 cells. In this report, we present evidence that the wild-type activity of the tumor suppressor gene p53 is involved in the negative growth regulation of this model system. p53 genes encoding either a p53Val-135 or p53Pro-193 mutation express a highly stable p53 protein with a conformation-dependent loss of wild-type activity and the ability to eliminate any endogenous wild-type p53 activity in a dominant negative manner. In cotransfection assays, these mutant p53 genes are able to rescue REF52 cells from ras-induced growth arrest, resulting in established cell lines which express elevated levels of the ras oncoprotein and show morphological transformation. Full transformation, as assayed by tumor formation in nude mice, is found only in the p53Pro-193-plus-ras transfectants. These cells express higher levels of the ras protein than do the p53Val-135-plus-ras-transfected cells. Transfection of REF52 cells with ras alone or a full-length genomic wild-type p53 plus ras results in growth arrest and lethality. Therefore, the selective event for p53 inactivation or loss during tumor progression may be to overcome a cell cycle restriction induced by oncogene overexpression (ras). These results suggest that a normal function of p53 may be to mediate negative growth regulation in response to ras or other proliferative inducing signals.

scholarly journals Mutant p53 elicits context-dependent pro-tumorigenic phenotypes

Oncogene ◽  
2021 ◽  
Author(s):  
Jennifer J. McCann ◽  
Irina A. Vasilevskaya ◽  
Christopher McNair ◽  
Peter Gallagher ◽  
Neermala Poudel Neupane ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Tumor Suppressor ◽  
Dna Binding ◽  
Mutant P53 ◽  
Wild Type ◽  
P53 Expression ◽  
Transcriptional Profiles ◽  
Cancer Types ◽  
Context Dependent ◽  
Wild Type P53

AbstractThe tumor suppressor gene TP53 is the most frequently mutated gene in numerous cancer types, including prostate cancer (PCa). Specifically, missense mutations in TP53 are selectively enriched in PCa, and cluster to particular “hot spots” in the p53 DNA binding domain with mutation at the R273 residue occurring most frequently. While this residue is similarly mutated to R273C-p53 or R273H-p53 in all cancer types examined, in PCa selective enrichment of R273C-p53 is observed. Importantly, examination of clinical datasets indicated that TP53 heterozygosity can either be maintained or loss of heterozygosity (LOH) occurs. Thus, to mimic tumor-associated mutant p53, R273C-p53 and R273H-p53 isogenic PCa models were developed in the presence or absence of wild-type p53. In the absence of wild-type p53, both R273C-p53 and R273H-p53 exhibited similar loss of DNA binding, transcriptional profiles, and loss of canonical tumor suppressor functions associated with wild-type p53. In the presence of wild-type p53 expression, both R273C-p53 and R273H-p53 supported canonical p53 target gene expression yet elicited distinct cistromic and transcriptional profiles when compared to each other. Moreover, heterozygous modeling of R273C-p53 or R273H-p53 expression resulted in distinct phenotypic outcomes in vitro and in vivo. Thus, mutant p53 acts in a context-dependent manner to elicit pro-tumorigenic transcriptional profiles, providing critical insight into mutant p53-mediated prostate cancer progression.

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