Activation of ERK and p38 Reduces AZD8055-Mediated Inhibition of Protein Synthesis in Hepatocellular Carcinoma HepG2 Cell Line

Protein synthesis is important for maintaining cellular homeostasis under various stress responses. In this study, we screened an anticancer drug library to select compounds with translational repression functions. AZD8055, an ATP-competitive mechanistic target of rapamycin complex 1/2 (mTORC1/2) in...

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Autores principales:	Ha-yeon Jee, Yoon-Gyeong Lee, Sol Lee, Rosalie Elvira, Hye-eun Seo, Ji-Yeon Lee, Jaeseok Han, Kyungho Lee
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	4E-BP1 AZD8055 ERK1/2 mTORC1/2 inhibitor p38 protein synthesis Biology (General) QH301-705.5 Chemistry QD1-999
Acceso en línea:	https://doaj.org/article/c42d7c13f2034c5081a43856736bd650
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spelling	oai:doaj.org-article:c42d7c13f2034c5081a43856736bd6502021-11-11T17:15:37ZActivation of ERK and p38 Reduces AZD8055-Mediated Inhibition of Protein Synthesis in Hepatocellular Carcinoma HepG2 Cell Line10.3390/ijms2221118241422-00671661-6596https://doaj.org/article/c42d7c13f2034c5081a43856736bd6502021-10-01T00:00:00Zhttps://www.mdpi.com/1422-0067/22/21/11824https://doaj.org/toc/1661-6596https://doaj.org/toc/1422-0067Protein synthesis is important for maintaining cellular homeostasis under various stress responses. In this study, we screened an anticancer drug library to select compounds with translational repression functions. AZD8055, an ATP-competitive mechanistic target of rapamycin complex 1/2 (mTORC1/2) inhibitor, was selected as a translational suppressor. AZD8055 inhibited protein synthesis in mouse embryonic fibroblasts and hepatocellular carcinoma HepG2 cells. Extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase (MAPK) were activated during the early phase of mTORC1/2 inhibition by AZD8055 treatment. Combined treatment of AZD8055 with the MAPK kinase1/2 (MEK1/2) inhibitor refametinib or the p38 inhibitor SB203580 markedly decreased translation in HepG2 cells. Thus, the inhibition of ERK1/2 or p38 may enhance the efficacy of AZD8055-mediated inhibition of protein synthesis. In addition, AZD8055 down-regulated the phosphorylation of eukaryotic initiation factor 4E-binding protein 1 (4E-BP1), and AZD8055-induced phosphorylation of ERK1/2 and p38 had no effect on phosphorylation status of 4E-BP1. Interestingly, AZD8055 modulated the <i>4E-BP1</i> mRNA pool by up-regulating ERK1/2 and p38 pathways. Together, these results suggest that AZD8055-induced activation of MAPKs interferes with inhibition of protein synthesis at an early stage of mTORC1/2 inhibition, and that it may contribute to the development of resistance to mTORC1/2 inhibitors.Ha-yeon JeeYoon-Gyeong LeeSol LeeRosalie ElviraHye-eun SeoJi-Yeon LeeJaeseok HanKyungho LeeMDPI AGarticle4E-BP1AZD8055ERK1/2mTORC1/2 inhibitorp38protein synthesisBiology (General)QH301-705.5ChemistryQD1-999ENInternational Journal of Molecular Sciences, Vol 22, Iss 11824, p 11824 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	4E-BP1 AZD8055 ERK1/2 mTORC1/2 inhibitor p38 protein synthesis Biology (General) QH301-705.5 Chemistry QD1-999
spellingShingle	4E-BP1 AZD8055 ERK1/2 mTORC1/2 inhibitor p38 protein synthesis Biology (General) QH301-705.5 Chemistry QD1-999 Ha-yeon Jee Yoon-Gyeong Lee Sol Lee Rosalie Elvira Hye-eun Seo Ji-Yeon Lee Jaeseok Han Kyungho Lee Activation of ERK and p38 Reduces AZD8055-Mediated Inhibition of Protein Synthesis in Hepatocellular Carcinoma HepG2 Cell Line
description	Protein synthesis is important for maintaining cellular homeostasis under various stress responses. In this study, we screened an anticancer drug library to select compounds with translational repression functions. AZD8055, an ATP-competitive mechanistic target of rapamycin complex 1/2 (mTORC1/2) inhibitor, was selected as a translational suppressor. AZD8055 inhibited protein synthesis in mouse embryonic fibroblasts and hepatocellular carcinoma HepG2 cells. Extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase (MAPK) were activated during the early phase of mTORC1/2 inhibition by AZD8055 treatment. Combined treatment of AZD8055 with the MAPK kinase1/2 (MEK1/2) inhibitor refametinib or the p38 inhibitor SB203580 markedly decreased translation in HepG2 cells. Thus, the inhibition of ERK1/2 or p38 may enhance the efficacy of AZD8055-mediated inhibition of protein synthesis. In addition, AZD8055 down-regulated the phosphorylation of eukaryotic initiation factor 4E-binding protein 1 (4E-BP1), and AZD8055-induced phosphorylation of ERK1/2 and p38 had no effect on phosphorylation status of 4E-BP1. Interestingly, AZD8055 modulated the <i>4E-BP1</i> mRNA pool by up-regulating ERK1/2 and p38 pathways. Together, these results suggest that AZD8055-induced activation of MAPKs interferes with inhibition of protein synthesis at an early stage of mTORC1/2 inhibition, and that it may contribute to the development of resistance to mTORC1/2 inhibitors.
format	article
author	Ha-yeon Jee Yoon-Gyeong Lee Sol Lee Rosalie Elvira Hye-eun Seo Ji-Yeon Lee Jaeseok Han Kyungho Lee
author_facet	Ha-yeon Jee Yoon-Gyeong Lee Sol Lee Rosalie Elvira Hye-eun Seo Ji-Yeon Lee Jaeseok Han Kyungho Lee
author_sort	Ha-yeon Jee
title	Activation of ERK and p38 Reduces AZD8055-Mediated Inhibition of Protein Synthesis in Hepatocellular Carcinoma HepG2 Cell Line
title_short	Activation of ERK and p38 Reduces AZD8055-Mediated Inhibition of Protein Synthesis in Hepatocellular Carcinoma HepG2 Cell Line
title_full	Activation of ERK and p38 Reduces AZD8055-Mediated Inhibition of Protein Synthesis in Hepatocellular Carcinoma HepG2 Cell Line
title_fullStr	Activation of ERK and p38 Reduces AZD8055-Mediated Inhibition of Protein Synthesis in Hepatocellular Carcinoma HepG2 Cell Line
title_full_unstemmed	Activation of ERK and p38 Reduces AZD8055-Mediated Inhibition of Protein Synthesis in Hepatocellular Carcinoma HepG2 Cell Line
title_sort	activation of erk and p38 reduces azd8055-mediated inhibition of protein synthesis in hepatocellular carcinoma hepg2 cell line
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/c42d7c13f2034c5081a43856736bd650
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Activation of ERK and p38 Reduces AZD8055-Mediated Inhibition of Protein Synthesis in Hepatocellular Carcinoma HepG2 Cell Line

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