Gain of Function (GOF) Mutant p53 in Cancer—Current Therapeutic Approaches

Roszkowska, Katarzyna; Piecuch, Aleksandra; Sady, Maria; Gajewski, Zdzisław; Flis, Sylwia

doi:10.3390/ijms232113287

Cited by 19 publications

(17 citation statements)

References 110 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In addition, p53 aggregation has been related to the GoFs observed in cancer models ( Xu et al, 2011 ; Pedrote et al, 2020 ). Among these GoFs are increased invasion, altered migration ( Adorno et al, 2009 ; Muller et al, 2009 ), and drug resistance ( Shetzer et al, 2014 ; Xu et al, 2020 ; Roszkowska et al, 2022 ). We sought to evaluate the functional effects of PRIMA-1 on GoF properties in Huh-7 cells.…”

Section: Resultsmentioning

confidence: 99%

PRIMA-1 inhibits Y220C p53 amyloid aggregation and synergizes with cisplatin in hepatocellular carcinoma

Paz

Ferretti

Martins-Dinis

et al. 2023

Front. Mol. Biosci.

View full text Add to dashboard Cite

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide. Although many therapeutic options are available, several factors, including the presence of p53 mutations, impact tumor development and therapeutic resistance. TP53 is the second most frequently mutated gene in HCC, comprising more than 30% of cases. Mutations in p53 result in the formation of amyloid aggregates that promote tumor progression. The use of PRIMA-1, a small molecule capable of restoring p53, is a therapeutic strategy to pharmacologically target the amyloid state mutant p53. In this study, we characterize an HCC mutant p53 model for the study of p53 amyloid aggregation in HCC cell lines, from in silico analysis of p53 mutants to a 3D-cell culture model and demonstrate the unprecedented inhibition of Y220C mutant p53 aggregation by PRIMA-1. In addition, our data show beneficial effects of PRIMA-1 in several “gain of function” properties of mutant-p53 cancer cells, including migration, adhesion, proliferation, and drug resistance. We also demonstrate that the combination of PRIMA-1 and cisplatin is a promising approach for HCC therapy. Taken together, our data support the premise that targeting the amyloid-state of mutant p53 may be an attractive therapeutic approach for HCC, and highlight PRIMA-1 as a new candidate for combination therapy with cisplatin.

show abstract

Section: Resultsmentioning

confidence: 99%

PRIMA-1 inhibits Y220C p53 amyloid aggregation and synergizes with cisplatin in hepatocellular carcinoma

Paz

Ferretti

Martins-Dinis

et al. 2023

Front. Mol. Biosci.

View full text Add to dashboard Cite

show abstract

“…In CRC, the TP53 gene is mutated in 43% of tumors, and the remaining tumors often have compromised p53 functioning due to changes in regulatory mechanisms [ 50 ]. The gain of function and loss of function activities of mutated TP53 is linked to cell proliferation, metastasis, and invasion that is further associated with CRC progression and other types of cancers [ 50 , 51 , 52 ]. Interactions of p53 with other transcription factors can enhance or repress their activity.…”

Section: Discussionmentioning

confidence: 99%

Combinatorial Network of Transcriptional and miRNA Regulation in Colorectal Cancer

Kumar

Mahmoud

Tashkandi

et al. 2023

IJMS

View full text Add to dashboard Cite

Colorectal cancer is one of the leading causes of cancer-associated mortality across the worldwide. One of the major challenges in colorectal cancer is the understanding of the regulatory mechanisms of biological molecules. In this study, we aimed to identify novel key molecules in colorectal cancer by using a computational systems biology approach. We constructed the colorectal protein–protein interaction network which followed hierarchical scale-free nature. We identified TP53, CTNBB1, AKT1, EGFR, HRAS, JUN, RHOA, and EGF as bottleneck-hubs. The HRAS showed the largest interacting strength with functional subnetworks, having strong correlation with protein phosphorylation, kinase activity, signal transduction, and apoptotic processes. Furthermore, we constructed the bottleneck-hubs’ regulatory networks with their transcriptional (transcription factor) and post-transcriptional (miRNAs) regulators, which exhibited the important key regulators. We observed miR-429, miR-622, and miR-133b and transcription factors (EZH2, HDAC1, HDAC4, AR, NFKB1, and KLF4) regulates four bottleneck-hubs (TP53, JUN, AKT1 and EGFR) at the motif level. In future, biochemical investigation of the observed key regulators could provide further understanding about their role in the pathophysiology of colorectal cancer.

show abstract

“…The TP53 gene mutations can be mainly categorized into two types, such as contact mutants (R248Q, R273H, and R248W) and conformational mutants (G245S, R175H, R249S, and R282H) [ 30 ]. Both the mutants type are well known to affect the DNA binding domain (DBD) [ 31 ].…”

Section: Amyloid/mutant P53 Gain-of-functionmentioning

confidence: 99%

Transition of amyloid/mutant p53 from tumor suppressor to an oncogene and therapeutic approaches to ameliorate metastasis and cancer stemness

et al. 2022

View full text Add to dashboard Cite

The tumor suppressor p53 when undergoes amyloid formation confers several gain-of-function (GOF) activities that affect molecular pathways crucial for tumorigenesis and progression like some of the p53 mutants. Even after successful cancer treatment, metastasis and recurrence can result in poor survival rates. The major cause of recurrence is mainly the remnant cancer cells with stem cell-like properties, which are resistant to any chemotherapy treatment. Several studies have demonstrated the role of p53 mutants in exacerbating cancer stemness properties and epithelial-mesenchymal transition in these remnant cancer cells. Analyzing the amyloid/mutant p53-mediated signaling pathways that trigger metastasis, relapse or chemoresistance may be helpful for the development of novel or improved individualized treatment plans. In this review, we discuss the changes in the metabolic pathways such as mevalonate pathway and different signaling pathways such as TGF-β, PI3K/AKT/mTOR, NF-κB and Wnt due to p53 amyloid formation, or mutation. In addition to this, we have discussed the role of the regulatory microRNAs and lncRNAs linked with the mutant or amyloid p53 in human malignancies. Such changes promote tumor spread, potential recurrence, and stemness. Importantly, this review discusses the cancer therapies that target either mutant or amyloid p53, restore wild-type functions, and exploit the synthetic lethal interactions with mutant p53.

show abstract

Gain of Function (GOF) Mutant p53 in Cancer—Current Therapeutic Approaches

Cited by 19 publications

References 110 publications

PRIMA-1 inhibits Y220C p53 amyloid aggregation and synergizes with cisplatin in hepatocellular carcinoma

PRIMA-1 inhibits Y220C p53 amyloid aggregation and synergizes with cisplatin in hepatocellular carcinoma

Combinatorial Network of Transcriptional and miRNA Regulation in Colorectal Cancer

Transition of amyloid/mutant p53 from tumor suppressor to an oncogene and therapeutic approaches to ameliorate metastasis and cancer stemness

Contact Info

Product

Resources

About