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ETHE1 Accelerates Triple-Negative Breast Cancer Metastasis by Activating GCN2/eIF2α/ATF4 Signaling

Triple-negative breast cancer (TNBC) is the most fatal subtype of breast cancer; however, effective treatment strategies for TNBC are lacking. Therefore, it is important to explore the mechanism of TNBC metastasis and identify its therapeutic targets. Dysregulation of ETHE1 leads to ethylmalonic enc...

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Autores principales: Yang, Shao-Ying, Liao, Li, Hu, Shu-Yuan, Deng, Ling, Andriani, Lisa, Zhang, Tai-Mei, Zhang, Yin-Ling, Ma, Xiao-Yan, Zhang, Fang-Lin, Liu, Ying-Ying, Li, Da-Qiang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10572406/
https://www.ncbi.nlm.nih.gov/pubmed/37834012
http://dx.doi.org/10.3390/ijms241914566
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author Yang, Shao-Ying
Liao, Li
Hu, Shu-Yuan
Deng, Ling
Andriani, Lisa
Zhang, Tai-Mei
Zhang, Yin-Ling
Ma, Xiao-Yan
Zhang, Fang-Lin
Liu, Ying-Ying
Li, Da-Qiang
author_facet Yang, Shao-Ying
Liao, Li
Hu, Shu-Yuan
Deng, Ling
Andriani, Lisa
Zhang, Tai-Mei
Zhang, Yin-Ling
Ma, Xiao-Yan
Zhang, Fang-Lin
Liu, Ying-Ying
Li, Da-Qiang
author_sort Yang, Shao-Ying
collection PubMed
description Triple-negative breast cancer (TNBC) is the most fatal subtype of breast cancer; however, effective treatment strategies for TNBC are lacking. Therefore, it is important to explore the mechanism of TNBC metastasis and identify its therapeutic targets. Dysregulation of ETHE1 leads to ethylmalonic encephalopathy in humans; however, the role of ETHE1 in TNBC remains elusive. Stable cell lines with ETHE1 overexpression or knockdown were constructed to explore the biological functions of ETHE1 during TNBC progression in vitro and in vivo. Mass spectrometry was used to analyze the molecular mechanism through which ETHE1 functions in TNBC progression. ETHE1 had no impact on TNBC cell proliferation and xenograft tumor growth but promoted TNBC cell migration and invasion in vitro and lung metastasis in vivo. The effect of ETHE1 on TNBC cell migratory potential was independent of its enzymatic activity. Mechanistic investigations revealed that ETHE1 interacted with eIF2α and enhanced its phosphorylation by promoting the interaction between eIF2α and GCN2. Phosphorylated eIF2α in turn upregulated the expression of ATF4, a transcriptional activator of genes involved in cell migration and tumor metastasis. Notably, inhibition of eIF2α phosphorylation through ISRIB or ATF4 knockdown partially abolished the tumor-promoting effect of ETHE1 overexpression. ETHE1 has a functional and mechanistic role in TNBC metastasis and offers a new therapeutic strategy for targeting ETHE1-propelled TNBC using ISRIB.
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spelling pubmed-105724062023-10-14 ETHE1 Accelerates Triple-Negative Breast Cancer Metastasis by Activating GCN2/eIF2α/ATF4 Signaling Yang, Shao-Ying Liao, Li Hu, Shu-Yuan Deng, Ling Andriani, Lisa Zhang, Tai-Mei Zhang, Yin-Ling Ma, Xiao-Yan Zhang, Fang-Lin Liu, Ying-Ying Li, Da-Qiang Int J Mol Sci Article Triple-negative breast cancer (TNBC) is the most fatal subtype of breast cancer; however, effective treatment strategies for TNBC are lacking. Therefore, it is important to explore the mechanism of TNBC metastasis and identify its therapeutic targets. Dysregulation of ETHE1 leads to ethylmalonic encephalopathy in humans; however, the role of ETHE1 in TNBC remains elusive. Stable cell lines with ETHE1 overexpression or knockdown were constructed to explore the biological functions of ETHE1 during TNBC progression in vitro and in vivo. Mass spectrometry was used to analyze the molecular mechanism through which ETHE1 functions in TNBC progression. ETHE1 had no impact on TNBC cell proliferation and xenograft tumor growth but promoted TNBC cell migration and invasion in vitro and lung metastasis in vivo. The effect of ETHE1 on TNBC cell migratory potential was independent of its enzymatic activity. Mechanistic investigations revealed that ETHE1 interacted with eIF2α and enhanced its phosphorylation by promoting the interaction between eIF2α and GCN2. Phosphorylated eIF2α in turn upregulated the expression of ATF4, a transcriptional activator of genes involved in cell migration and tumor metastasis. Notably, inhibition of eIF2α phosphorylation through ISRIB or ATF4 knockdown partially abolished the tumor-promoting effect of ETHE1 overexpression. ETHE1 has a functional and mechanistic role in TNBC metastasis and offers a new therapeutic strategy for targeting ETHE1-propelled TNBC using ISRIB. MDPI 2023-09-26 /pmc/articles/PMC10572406/ /pubmed/37834012 http://dx.doi.org/10.3390/ijms241914566 Text en © 2023 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
Yang, Shao-Ying
Liao, Li
Hu, Shu-Yuan
Deng, Ling
Andriani, Lisa
Zhang, Tai-Mei
Zhang, Yin-Ling
Ma, Xiao-Yan
Zhang, Fang-Lin
Liu, Ying-Ying
Li, Da-Qiang
ETHE1 Accelerates Triple-Negative Breast Cancer Metastasis by Activating GCN2/eIF2α/ATF4 Signaling
title ETHE1 Accelerates Triple-Negative Breast Cancer Metastasis by Activating GCN2/eIF2α/ATF4 Signaling
title_full ETHE1 Accelerates Triple-Negative Breast Cancer Metastasis by Activating GCN2/eIF2α/ATF4 Signaling
title_fullStr ETHE1 Accelerates Triple-Negative Breast Cancer Metastasis by Activating GCN2/eIF2α/ATF4 Signaling
title_full_unstemmed ETHE1 Accelerates Triple-Negative Breast Cancer Metastasis by Activating GCN2/eIF2α/ATF4 Signaling
title_short ETHE1 Accelerates Triple-Negative Breast Cancer Metastasis by Activating GCN2/eIF2α/ATF4 Signaling
title_sort ethe1 accelerates triple-negative breast cancer metastasis by activating gcn2/eif2α/atf4 signaling
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10572406/
https://www.ncbi.nlm.nih.gov/pubmed/37834012
http://dx.doi.org/10.3390/ijms241914566
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