Nonselective TRPC channel inhibition and suppression of aminoglycoside-induced premature termination codon readthrough by the small molecule AC1903

Baradaran‐Heravi, Alireza; Bauer, Claudia; Pickles, Isabelle B.; Hosseini-Farahabadi, Sara; Balgi, Aruna D.; Choi, Kunho; Linley, Deborah M; Beech, David J; Roberge, Michel; Bon, Robin S.

doi:10.1016/j.jbc.2021.101546

Cited by 13 publications

(7 citation statements)

References 82 publications

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“…Studies have shown that alterations in calcium metabolism, such as changes in the expression or activity of calcium channels, pumps, and exchangers, can lead to the development of PTC ( 12 , 37 , 38 ). For example, mutations in genes encoding calcium channels and pumps, such as TRPC3, TRPM7, and SERCA2, have been identified in PTC patients ( 39 , 40 ). These mutations have been associated with an increased risk of tumor recurrence and a poorer prognosis.…”

Section: Discussionmentioning

confidence: 99%

Identification of calcium metabolism related score associated with the poor outcome in papillary thyroid carcinoma

Yan

2023

Front. Oncol.

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IntroductionPapillary thyroid carcinoma is a type of thyroid cancer that exhibits significant variability in prognosis. Extensive research indicates that the impaired signaling of 1,25(OH)2D3-VDR may be a crucial factor in the development and progression of PTC.MethodsTo investigate this further, Integrated analysis mRNA expression information from The Cancer Genome Atlas and GEO, we compared gene expression in cancer and normal tissues and identified differentially expressed genes (DEGs). Through this analysis, we identified DEGs and calculated risk estimates for seven genetic markers.ResultsSubsequently, we constructed predictive models using LASSO-Cox regression to test the predictive value of these markers. Our results revealed that 64 calcium metabolism-related genes showed significant differences between tumor and normal tissues. Ten of the identified DEGs were significantly associated with overall survival, indicating their potential role in disease progression. Using the average risk score for the seven genetic markers, we divided patients into high- and low-risk groups. We found that patients in the low-risk group had significantly better overall survival than those in the high-risk group, highlighting the importance of these genetic markers in predicting prognosis. Further analysis using Cox regression demonstrated that the risk levels had independent predictive power. Additionally, we conducted functional analysis of the identified genetic markers, which showed significant differences in immune status between the two patient groups. We also investigated the effect of these calcium metabolism-related genes on thyroid cancer biological functions, immune microenvironment, and drug resistance.DiscussionOur findings provide evidence of a novel genetic signature associated with calcium metabolism, which can predict prognosis in patients with PTC. These results may have significant implications for the development of new diagnostic and therapeutic approaches to improve outcomes for PTC patients.

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Section: Discussionmentioning

confidence: 99%

Identification of calcium metabolism related score associated with the poor outcome in papillary thyroid carcinoma

Yan

2023

Front. Oncol.

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“…Recent studies also investigated the role of nonselective and selective transient receptor potential channel (TRPC) calcium channels in controlling SCR via cellular uptake. AC1903, a TRPC5 inhibitor, successfully suppressed G418 uptake and, hence, SCR in junctional EB patient‐derived keratinocytes with a nonsense mutation in the COL17A1 gene 56 …”

Section: Aminoglycoside Antibioticsmentioning

confidence: 99%

Stop codon readthrough as a treatment option for epidermolysis bullosa—Where we are and where we are going

Zandanell,

Wießner,

Bauer

et al. 2024

Experimental Dermatology

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In the context of rare genetic diseases caused by nonsense mutations, the concept of induced stop codon readthrough (SCR) represents an attractive avenue in the ongoing search for improved treatment options. Epidermolysis bullosa (EB)—exemplary for this group of diseases—describes a diverse group of rare, blistering genodermatoses. Characterized by extreme skin fragility upon minor mechanical trauma, the most severe forms often result from nonsense mutations that lead to premature translation termination and loss of function of essential proteins at the dermo‐epidermal junction. Since no curative interventions are currently available, medical care is mainly limited to alleviating symptoms and preventing complications. Complementary to attempts of gene, cell and protein therapy in EB, SCR represents a promising medical alternative. While gentamicin has already been examined in several clinical trials involving EB, other potent SCR inducers, such as ataluren, may also show promise in treating the hitherto non‐curative disease. In addition to the extensively studied aminoglycosides and their derivatives, several other substance classes—non‐aminoglycoside antibiotics and non‐aminoglycoside compounds—are currently under investigation. The extensive data gathered in numerous in vitro experiments and the perspectives they reveal in the clinical setting will be discussed in this review.

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“…Very recently, Baradaran-Heravi et al demonstrated that TRPC cation channels influence readthrough efficiencies by controlling the cellular uptake of aminoglycosides. The inhibition of the TRPC5 channel with a small molecule (AC1903) reduced intracellular concentrations of G418 and consequently reduced the induction of PTC-readthrough in a cancer cell line (harboring a homozygous p53 nonsense mutation) and in junctional epidermolysis bullosa (JEB) patient-derived keratinocytes (harboring a homozygous mutation in COL17A1 ) [ 119 ].…”

Section: Induction Of Nonsense Suppressionmentioning

confidence: 99%

Emerging Personalized Opportunities for Enhancing Translational Readthrough in Rare Genetic Diseases and Beyond

Wagner

Wießner

Friedrich

et al. 2023

IJMS

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Nonsense mutations trigger premature translation termination and often give rise to prevalent and rare genetic diseases. Consequently, the pharmacological suppression of an unscheduled stop codon represents an attractive treatment option and is of high clinical relevance. At the molecular level, the ability of the ribosome to continue translation past a stop codon is designated stop codon readthrough (SCR). SCR of disease-causing premature termination codons (PTCs) is minimal but small molecule interventions, such as treatment with aminoglycoside antibiotics, can enhance its frequency. In this review, we summarize the current understanding of translation termination (both at PTCs and at cognate stop codons) and highlight recently discovered pathways that influence its fidelity. We describe the mechanisms involved in the recognition and readthrough of PTCs and report on SCR-inducing compounds currently explored in preclinical research and clinical trials. We conclude by reviewing the ongoing attempts of personalized nonsense suppression therapy in different disease contexts, including the genetic skin condition epidermolysis bullosa.

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Nonselective TRPC channel inhibition and suppression of aminoglycoside-induced premature termination codon readthrough by the small molecule AC1903

Cited by 13 publications

References 82 publications

Identification of calcium metabolism related score associated with the poor outcome in papillary thyroid carcinoma

Identification of calcium metabolism related score associated with the poor outcome in papillary thyroid carcinoma

Stop codon readthrough as a treatment option for epidermolysis bullosa—Where we are and where we are going

Emerging Personalized Opportunities for Enhancing Translational Readthrough in Rare Genetic Diseases and Beyond

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