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PTC124 Rescues Nonsense Mutation of Two Tumor Suppressor Genes NOTCH1 and FAT1 to Repress HNSCC Cell Proliferation

(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 anothe...

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Autores principales: Wu, Ming-Han, Lu, Rui-Yu, Yu, Si-Jie, Tsai, Yi-Zhen, Lin, Ying-Chen, Bai, Zhi-Yu, Liao, Ruo-Yu, Hsu, Yi-Chiang, Chen, Chia-Chi, Cai, Bi-He
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9687978/
https://www.ncbi.nlm.nih.gov/pubmed/36428516
http://dx.doi.org/10.3390/biomedicines10112948
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author Wu, Ming-Han
Lu, Rui-Yu
Yu, Si-Jie
Tsai, Yi-Zhen
Lin, Ying-Chen
Bai, Zhi-Yu
Liao, Ruo-Yu
Hsu, Yi-Chiang
Chen, Chia-Chi
Cai, Bi-He
author_facet Wu, Ming-Han
Lu, Rui-Yu
Yu, Si-Jie
Tsai, Yi-Zhen
Lin, Ying-Chen
Bai, Zhi-Yu
Liao, Ruo-Yu
Hsu, Yi-Chiang
Chen, Chia-Chi
Cai, Bi-He
author_sort Wu, Ming-Han
collection PubMed
description (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 FAT1 in HSNCC (2) Methods: DOK (with NOTCH1 Y550X) or HO-1-u-1 (with FAT1 E378X) HNSCC cells were treated with PTC124, and the NOTCH1 or FAT1 expression, cell viability, and NOTCH1- or FAT1-related downstream gene profiles were assayed. (3) Results: PTC124 was able to induce NOTCH1 or FAT1 expression in DOK and HO-1-u-1 cells. PTC124 was able to upregulate NOTCH downstream genes HES5, AJUBA, and ADAM10 in DOK cells. PTC124 enhanced DDIT4, which is under the control of the FAT1–YAP1 pathway, in HO-1-u-1 cells. FLI-06 (a NOTCH signaling inhibitor) reversed PTC124-mediated cell growth inhibition in DOK cells. PTC124 could reverse TT-10 (a YAP signaling activator)-mediated HO-1-u-1 cell proliferation. (4) Conclusions: PTC124 can rescue nonsense mutation of NOTCH1 and FAT1 to repress HNSCC cell proliferation.
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spelling pubmed-96879782022-11-25 PTC124 Rescues Nonsense Mutation of Two Tumor Suppressor Genes NOTCH1 and FAT1 to Repress HNSCC Cell Proliferation Wu, Ming-Han Lu, Rui-Yu Yu, Si-Jie Tsai, Yi-Zhen Lin, Ying-Chen Bai, Zhi-Yu Liao, Ruo-Yu Hsu, Yi-Chiang Chen, Chia-Chi Cai, Bi-He Biomedicines Article (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 FAT1 in HSNCC (2) Methods: DOK (with NOTCH1 Y550X) or HO-1-u-1 (with FAT1 E378X) HNSCC cells were treated with PTC124, and the NOTCH1 or FAT1 expression, cell viability, and NOTCH1- or FAT1-related downstream gene profiles were assayed. (3) Results: PTC124 was able to induce NOTCH1 or FAT1 expression in DOK and HO-1-u-1 cells. PTC124 was able to upregulate NOTCH downstream genes HES5, AJUBA, and ADAM10 in DOK cells. PTC124 enhanced DDIT4, which is under the control of the FAT1–YAP1 pathway, in HO-1-u-1 cells. FLI-06 (a NOTCH signaling inhibitor) reversed PTC124-mediated cell growth inhibition in DOK cells. PTC124 could reverse TT-10 (a YAP signaling activator)-mediated HO-1-u-1 cell proliferation. (4) Conclusions: PTC124 can rescue nonsense mutation of NOTCH1 and FAT1 to repress HNSCC cell proliferation. MDPI 2022-11-16 /pmc/articles/PMC9687978/ /pubmed/36428516 http://dx.doi.org/10.3390/biomedicines10112948 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Wu, Ming-Han
Lu, Rui-Yu
Yu, Si-Jie
Tsai, Yi-Zhen
Lin, Ying-Chen
Bai, Zhi-Yu
Liao, Ruo-Yu
Hsu, Yi-Chiang
Chen, Chia-Chi
Cai, Bi-He
PTC124 Rescues Nonsense Mutation of Two Tumor Suppressor Genes NOTCH1 and FAT1 to Repress HNSCC Cell Proliferation
title PTC124 Rescues Nonsense Mutation of Two Tumor Suppressor Genes NOTCH1 and FAT1 to Repress HNSCC Cell Proliferation
title_full PTC124 Rescues Nonsense Mutation of Two Tumor Suppressor Genes NOTCH1 and FAT1 to Repress HNSCC Cell Proliferation
title_fullStr PTC124 Rescues Nonsense Mutation of Two Tumor Suppressor Genes NOTCH1 and FAT1 to Repress HNSCC Cell Proliferation
title_full_unstemmed PTC124 Rescues Nonsense Mutation of Two Tumor Suppressor Genes NOTCH1 and FAT1 to Repress HNSCC Cell Proliferation
title_short PTC124 Rescues Nonsense Mutation of Two Tumor Suppressor Genes NOTCH1 and FAT1 to Repress HNSCC Cell Proliferation
title_sort ptc124 rescues nonsense mutation of two tumor suppressor genes notch1 and fat1 to repress hnscc cell proliferation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9687978/
https://www.ncbi.nlm.nih.gov/pubmed/36428516
http://dx.doi.org/10.3390/biomedicines10112948
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