Abstract:(1) Background: PTC124 (Ataluren) is an investigational drug for the treatment of nonsense mutation-mediated genetic diseases. With the exception of the TP53 tumor suppressor gene, there has been little research on cancers with nonsense mutation. By conducting a database search, we found that another two tumor suppressor genes, NOTCH1 and FAT1, have a high nonsense mutation rate in head and neck squamous cell carcinoma (HNSCC). PTC124 may re-express the functional NOTCH1 or FAT1 in nonsense mutation NOTCH1 or … Show more
“… 500 Wu et al found that PTC124 (Ataluren) could help HNSCC cells re-express functional Notch1 to substitute the nonsense mutation Notch1, thus preventing the proliferation of HNSCC cells. 501 Taken together, these findings provide evidence that Notch functions as tumor suppressor in relation to SCC, and SCC may be a cancer subtype that could benefit from specific activation of the Notch receptor. Fig.…”
Section: The Mechanism Of Notch Signaling Patyway-mediated Tumorigene...mentioning
Notch signaling, renowned for its role in regulating cell fate, organ development, and tissue homeostasis across metazoans, is highly conserved throughout evolution. The Notch receptor and its ligands are transmembrane proteins containing epidermal growth factor-like repeat sequences, typically necessitating receptor-ligand interaction to initiate classical Notch signaling transduction. Accumulating evidence indicates that the Notch signaling pathway serves as both an oncogenic factor and a tumor suppressor in various cancer types. Dysregulation of this pathway promotes epithelial-mesenchymal transition and angiogenesis in malignancies, closely linked to cancer proliferation, invasion, and metastasis. Furthermore, the Notch signaling pathway contributes to maintaining stem-like properties in cancer cells, thereby enhancing cancer invasiveness. The regulatory role of the Notch signaling pathway in cancer metabolic reprogramming and the tumor microenvironment suggests its pivotal involvement in balancing oncogenic and tumor suppressive effects. Moreover, the Notch signaling pathway is implicated in conferring chemoresistance to tumor cells. Therefore, a comprehensive understanding of these biological processes is crucial for developing innovative therapeutic strategies targeting Notch signaling. This review focuses on the research progress of the Notch signaling pathway in cancers, providing in-depth insights into the potential mechanisms of Notch signaling regulation in the occurrence and progression of cancer. Additionally, the review summarizes pharmaceutical clinical trials targeting Notch signaling for cancer therapy, aiming to offer new insights into therapeutic strategies for human malignancies.
“… 500 Wu et al found that PTC124 (Ataluren) could help HNSCC cells re-express functional Notch1 to substitute the nonsense mutation Notch1, thus preventing the proliferation of HNSCC cells. 501 Taken together, these findings provide evidence that Notch functions as tumor suppressor in relation to SCC, and SCC may be a cancer subtype that could benefit from specific activation of the Notch receptor. Fig.…”
Section: The Mechanism Of Notch Signaling Patyway-mediated Tumorigene...mentioning
Notch signaling, renowned for its role in regulating cell fate, organ development, and tissue homeostasis across metazoans, is highly conserved throughout evolution. The Notch receptor and its ligands are transmembrane proteins containing epidermal growth factor-like repeat sequences, typically necessitating receptor-ligand interaction to initiate classical Notch signaling transduction. Accumulating evidence indicates that the Notch signaling pathway serves as both an oncogenic factor and a tumor suppressor in various cancer types. Dysregulation of this pathway promotes epithelial-mesenchymal transition and angiogenesis in malignancies, closely linked to cancer proliferation, invasion, and metastasis. Furthermore, the Notch signaling pathway contributes to maintaining stem-like properties in cancer cells, thereby enhancing cancer invasiveness. The regulatory role of the Notch signaling pathway in cancer metabolic reprogramming and the tumor microenvironment suggests its pivotal involvement in balancing oncogenic and tumor suppressive effects. Moreover, the Notch signaling pathway is implicated in conferring chemoresistance to tumor cells. Therefore, a comprehensive understanding of these biological processes is crucial for developing innovative therapeutic strategies targeting Notch signaling. This review focuses on the research progress of the Notch signaling pathway in cancers, providing in-depth insights into the potential mechanisms of Notch signaling regulation in the occurrence and progression of cancer. Additionally, the review summarizes pharmaceutical clinical trials targeting Notch signaling for cancer therapy, aiming to offer new insights into therapeutic strategies for human malignancies.
“…Four different p53 nonsense mutations had TGA-type pre-stop codons. Previously, 50 µ M of PTC124 could strongly re-express p53 in SAS HNSCC cells with the E336X mutation, which contains the TAG pre-stop codon [16]. The flowchart of this research and the map of p53 nonsense mutation clones are shown in Figure 4.…”
Section: Resultsmentioning
confidence: 89%
“…Recently, our research has shown that PTC124 can also rescue nonsense mutations in three tumor suppressor genes, p53, NOTCH1, and FAT1, leading to repression of head and neck squamous cell carcinoma (HNSCC) cell proliferation [16]. The p53 gene, encoding a protein with only 393 amino acid residues, has a cDNA of around 1.2 Kb [17].…”
(1) Background: A premature termination codon (PTC) can be induced by a type of point mutation known as a nonsense mutation, which occurs within the coding region. Approximately 3.8% of human cancer patients have nonsense mutations of p53. However, the non-aminoglycoside drug PTC124 has shown potential to promote PTC readthrough and rescue full-length proteins. The COSMIC database contains 201 types of p53 nonsense mutations in cancers. We built a simple and affordable method to create different nonsense mutation clones of p53 for the study of the PTC readthrough activity of PTC124. (2) Methods: A modified inverse PCR-based site-directed mutagenesis method was used to clone the four nonsense mutations of p53, including W91X, S94X, R306X, and R342X. Each clone was transfected into p53 null H1299 cells and then treated with 50 μM of PTC124. (3) Results: PTC124 induced p53 re-expression in H1299-R306X and H1299-R342X clones but not in H1299-W91X and H1299-S94X clones. (4) Conclusions: Our data showed that PTC124 more effectively rescued the C-terminal of p53 nonsense mutations than the N-terminal of p53 nonsense mutations. We introduced a fast and low-cost site-directed mutagenesis method to clone the different nonsense mutations of p53 for drug screening.
“…Furthermore it has been found that PTC124 can inhibit head and neck squamous cell carcinoma (HNSCC) cell proliferation by affecting nonsense mutations in two tumor suppressor genes, NOTCH1 and FAT1 (Wu et al, 2022a). Mutant UPF1 was found in pancreatic ductal adenocarcinoma, resulting in overactivated NMD, closely associated with elevated ASNS expression levels.…”
Section: B Practical Application Of Disease-centred Target Discovery ...mentioning
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