Cargando…

The antitumor activity of a novel GCN2 inhibitor in head and neck squamous cell carcinoma cell lines

BACKGROUND: General control nonderepressible 2 (GCN2) senses amino acid deprivation and activates activating transcription factor 4 (ATF4), which regulates many adaptive genes. We evaluated the impact of AST-0513, a novel GCN2 inhibitor, on the GCN2-ATF4 pathway. Additionally, we evaluated the antit...

Descripción completa

Detalles Bibliográficos
Autores principales: Lee, Jeongjae, Keam, Bhumsuk, Kim, Soyeon, Heo, Jung-Nyoung, Joung, Eunkyo, Kim, Miso, Kim, Tae Min, Kim, Dong-Wan, Heo, Dae Seog
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Neoplasia Press 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9694079/
https://www.ncbi.nlm.nih.gov/pubmed/36436443
http://dx.doi.org/10.1016/j.tranon.2022.101592
_version_ 1784837709007683584
author Lee, Jeongjae
Keam, Bhumsuk
Kim, Soyeon
Heo, Jung-Nyoung
Joung, Eunkyo
Kim, Miso
Kim, Tae Min
Kim, Dong-Wan
Heo, Dae Seog
author_facet Lee, Jeongjae
Keam, Bhumsuk
Kim, Soyeon
Heo, Jung-Nyoung
Joung, Eunkyo
Kim, Miso
Kim, Tae Min
Kim, Dong-Wan
Heo, Dae Seog
author_sort Lee, Jeongjae
collection PubMed
description BACKGROUND: General control nonderepressible 2 (GCN2) senses amino acid deprivation and activates activating transcription factor 4 (ATF4), which regulates many adaptive genes. We evaluated the impact of AST-0513, a novel GCN2 inhibitor, on the GCN2-ATF4 pathway. Additionally, we evaluated the antitumor effects of AST-0513 in amino acid deprivation in head and neck squamous cell carcinoma (HNSCC) cell lines. METHODS: GCN2 expression in HNSCC patient tissues was measured by immunohistochemistry. Five HNSCC cell lines (SNU-1041, SNU-1066, SNU-1076, Detroit-562, FaDu) grown under amino acid deprivation conditions, were treated with AST-0513. After AST-0513 treatment, cell proliferation was measured by CCK-8 assay. Flow cytometry was used to evaluate apoptosis and cell cycle phase. In addition, immunoblotting was performed to evaluate the effect of AST-0513 on the GCN2-ATF4 pathway, cell cycle arrest, and apoptosis. RESULTS: We demonstrated that GCN2 was highly expressed in HNSCC patient tissues. AST-0513 inhibited the GCN2-ATF4 pathway in all five HNSCC cell lines. Inhibiting the GCN2-ATF4 pathway during amino acid deprivation reduced HNSCC cell proliferation and prevented adaptation to nutrient stress. Moreover, AST-0513 treatment led to p21 and Cyclin B1 accumulation and G2/M phase cycle arrest. Also, apoptosis was increased, consistent with increased bax expression, increased bcl-xL phosphorylation, and decreased bcl-2 expression. CONCLUSION: A novel GCN2 inhibitor, AST-0513, inhibited the GCN2-ATF4 pathway and has antitumor activity that inhibits proliferation and promotes cell cycle arrest and apoptosis. Considering the high expression of GCN2 in HNSCC patients, these results suggest the potential role of GCN2 inhibitor for the treatment of HNSCC.
format Online
Article
Text
id pubmed-9694079
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher Neoplasia Press
record_format MEDLINE/PubMed
spelling pubmed-96940792022-12-05 The antitumor activity of a novel GCN2 inhibitor in head and neck squamous cell carcinoma cell lines Lee, Jeongjae Keam, Bhumsuk Kim, Soyeon Heo, Jung-Nyoung Joung, Eunkyo Kim, Miso Kim, Tae Min Kim, Dong-Wan Heo, Dae Seog Transl Oncol Original Research BACKGROUND: General control nonderepressible 2 (GCN2) senses amino acid deprivation and activates activating transcription factor 4 (ATF4), which regulates many adaptive genes. We evaluated the impact of AST-0513, a novel GCN2 inhibitor, on the GCN2-ATF4 pathway. Additionally, we evaluated the antitumor effects of AST-0513 in amino acid deprivation in head and neck squamous cell carcinoma (HNSCC) cell lines. METHODS: GCN2 expression in HNSCC patient tissues was measured by immunohistochemistry. Five HNSCC cell lines (SNU-1041, SNU-1066, SNU-1076, Detroit-562, FaDu) grown under amino acid deprivation conditions, were treated with AST-0513. After AST-0513 treatment, cell proliferation was measured by CCK-8 assay. Flow cytometry was used to evaluate apoptosis and cell cycle phase. In addition, immunoblotting was performed to evaluate the effect of AST-0513 on the GCN2-ATF4 pathway, cell cycle arrest, and apoptosis. RESULTS: We demonstrated that GCN2 was highly expressed in HNSCC patient tissues. AST-0513 inhibited the GCN2-ATF4 pathway in all five HNSCC cell lines. Inhibiting the GCN2-ATF4 pathway during amino acid deprivation reduced HNSCC cell proliferation and prevented adaptation to nutrient stress. Moreover, AST-0513 treatment led to p21 and Cyclin B1 accumulation and G2/M phase cycle arrest. Also, apoptosis was increased, consistent with increased bax expression, increased bcl-xL phosphorylation, and decreased bcl-2 expression. CONCLUSION: A novel GCN2 inhibitor, AST-0513, inhibited the GCN2-ATF4 pathway and has antitumor activity that inhibits proliferation and promotes cell cycle arrest and apoptosis. Considering the high expression of GCN2 in HNSCC patients, these results suggest the potential role of GCN2 inhibitor for the treatment of HNSCC. Neoplasia Press 2022-11-24 /pmc/articles/PMC9694079/ /pubmed/36436443 http://dx.doi.org/10.1016/j.tranon.2022.101592 Text en © 2022 Published by Elsevier Inc. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Original Research
Lee, Jeongjae
Keam, Bhumsuk
Kim, Soyeon
Heo, Jung-Nyoung
Joung, Eunkyo
Kim, Miso
Kim, Tae Min
Kim, Dong-Wan
Heo, Dae Seog
The antitumor activity of a novel GCN2 inhibitor in head and neck squamous cell carcinoma cell lines
title The antitumor activity of a novel GCN2 inhibitor in head and neck squamous cell carcinoma cell lines
title_full The antitumor activity of a novel GCN2 inhibitor in head and neck squamous cell carcinoma cell lines
title_fullStr The antitumor activity of a novel GCN2 inhibitor in head and neck squamous cell carcinoma cell lines
title_full_unstemmed The antitumor activity of a novel GCN2 inhibitor in head and neck squamous cell carcinoma cell lines
title_short The antitumor activity of a novel GCN2 inhibitor in head and neck squamous cell carcinoma cell lines
title_sort antitumor activity of a novel gcn2 inhibitor in head and neck squamous cell carcinoma cell lines
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9694079/
https://www.ncbi.nlm.nih.gov/pubmed/36436443
http://dx.doi.org/10.1016/j.tranon.2022.101592
work_keys_str_mv AT leejeongjae theantitumoractivityofanovelgcn2inhibitorinheadandnecksquamouscellcarcinomacelllines
AT keambhumsuk theantitumoractivityofanovelgcn2inhibitorinheadandnecksquamouscellcarcinomacelllines
AT kimsoyeon theantitumoractivityofanovelgcn2inhibitorinheadandnecksquamouscellcarcinomacelllines
AT heojungnyoung theantitumoractivityofanovelgcn2inhibitorinheadandnecksquamouscellcarcinomacelllines
AT joungeunkyo theantitumoractivityofanovelgcn2inhibitorinheadandnecksquamouscellcarcinomacelllines
AT kimmiso theantitumoractivityofanovelgcn2inhibitorinheadandnecksquamouscellcarcinomacelllines
AT kimtaemin theantitumoractivityofanovelgcn2inhibitorinheadandnecksquamouscellcarcinomacelllines
AT kimdongwan theantitumoractivityofanovelgcn2inhibitorinheadandnecksquamouscellcarcinomacelllines
AT heodaeseog theantitumoractivityofanovelgcn2inhibitorinheadandnecksquamouscellcarcinomacelllines
AT leejeongjae antitumoractivityofanovelgcn2inhibitorinheadandnecksquamouscellcarcinomacelllines
AT keambhumsuk antitumoractivityofanovelgcn2inhibitorinheadandnecksquamouscellcarcinomacelllines
AT kimsoyeon antitumoractivityofanovelgcn2inhibitorinheadandnecksquamouscellcarcinomacelllines
AT heojungnyoung antitumoractivityofanovelgcn2inhibitorinheadandnecksquamouscellcarcinomacelllines
AT joungeunkyo antitumoractivityofanovelgcn2inhibitorinheadandnecksquamouscellcarcinomacelllines
AT kimmiso antitumoractivityofanovelgcn2inhibitorinheadandnecksquamouscellcarcinomacelllines
AT kimtaemin antitumoractivityofanovelgcn2inhibitorinheadandnecksquamouscellcarcinomacelllines
AT kimdongwan antitumoractivityofanovelgcn2inhibitorinheadandnecksquamouscellcarcinomacelllines
AT heodaeseog antitumoractivityofanovelgcn2inhibitorinheadandnecksquamouscellcarcinomacelllines