Cancer-associated fibroblasts-mediated ATF4 expression promotes malignancy and gemcitabine resistance in pancreatic cancer via the TGF-β1/SMAD2/3 pathway and ABCC1 transactivation

Cancer-associated fibroblasts (CAFs) contribute to malignant progression and chemoresistance in pancreatic ductal adenocarcinoma (PDAC). However, little is known about the underlying mechanism. In this study, we investigated the potential role and mechanisms of activating transcription factor 4 (ATF...

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Autores principales: Wei, Lusheng, Lin, Qing, Lu, Yanan, Li, Guolin, Huang, Leyi, Fu, Zhiqiang, Chen, Rufu, Zhou, Quanbo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2021
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Article
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8007632/
https://www.ncbi.nlm.nih.gov/pubmed/33782384
http://dx.doi.org/10.1038/s41419-021-03574-2
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author Wei, Lusheng
Lin, Qing
Lu, Yanan
Li, Guolin
Huang, Leyi
Fu, Zhiqiang
Chen, Rufu
Zhou, Quanbo
author_facet Wei, Lusheng
Lin, Qing
Lu, Yanan
Li, Guolin
Huang, Leyi
Fu, Zhiqiang
Chen, Rufu
Zhou, Quanbo
author_sort Wei, Lusheng
collection PubMed
description Cancer-associated fibroblasts (CAFs) contribute to malignant progression and chemoresistance in pancreatic ductal adenocarcinoma (PDAC). However, little is known about the underlying mechanism. In this study, we investigated the potential role and mechanisms of activating transcription factor 4 (ATF4) in CAFs-induced malignancy and gemcitabine resistance. We demonstrated that ATF4 is overexpressed in PDAC and associated with a poor prognosis. Silencing ATF4 expression decreased proliferation, colony formation, migration, gemcitabine sensitivity, and sphere formation. Subsequently, we revealed that CAFs secrete TGF-β1 to upregulate the expression of ATF4 in PDAC cells via the SMAD2/3 pathway and induce cancer progression, cancer stemness, and gemcitabine resistance. Furthermore, we demonstrated that ATF4 directly binds to the ABCC1 promoter region to activate transcription. In summary, these data demonstrate that CAFs contribute to malignancy and gemcitabine resistance in PDAC by upregulating the expression of ATF4 via the TGF-β1/SMAD2/3 axis and highlight that ATF4 is an attractive therapeutic target for combating gemcitabine resistance in PDAC.
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spelling pubmed-80076322021-04-16 Cancer-associated fibroblasts-mediated ATF4 expression promotes malignancy and gemcitabine resistance in pancreatic cancer via the TGF-β1/SMAD2/3 pathway and ABCC1 transactivation Wei, Lusheng Lin, Qing Lu, Yanan Li, Guolin Huang, Leyi Fu, Zhiqiang Chen, Rufu Zhou, Quanbo Cell Death Dis Article Cancer-associated fibroblasts (CAFs) contribute to malignant progression and chemoresistance in pancreatic ductal adenocarcinoma (PDAC). However, little is known about the underlying mechanism. In this study, we investigated the potential role and mechanisms of activating transcription factor 4 (ATF4) in CAFs-induced malignancy and gemcitabine resistance. We demonstrated that ATF4 is overexpressed in PDAC and associated with a poor prognosis. Silencing ATF4 expression decreased proliferation, colony formation, migration, gemcitabine sensitivity, and sphere formation. Subsequently, we revealed that CAFs secrete TGF-β1 to upregulate the expression of ATF4 in PDAC cells via the SMAD2/3 pathway and induce cancer progression, cancer stemness, and gemcitabine resistance. Furthermore, we demonstrated that ATF4 directly binds to the ABCC1 promoter region to activate transcription. In summary, these data demonstrate that CAFs contribute to malignancy and gemcitabine resistance in PDAC by upregulating the expression of ATF4 via the TGF-β1/SMAD2/3 axis and highlight that ATF4 is an attractive therapeutic target for combating gemcitabine resistance in PDAC. Nature Publishing Group UK 2021-03-29 /pmc/articles/PMC8007632/ /pubmed/33782384 http://dx.doi.org/10.1038/s41419-021-03574-2 Text en © The Author(s) 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Wei, Lusheng
Lin, Qing
Lu, Yanan
Li, Guolin
Huang, Leyi
Fu, Zhiqiang
Chen, Rufu
Zhou, Quanbo
Cancer-associated fibroblasts-mediated ATF4 expression promotes malignancy and gemcitabine resistance in pancreatic cancer via the TGF-β1/SMAD2/3 pathway and ABCC1 transactivation
title Cancer-associated fibroblasts-mediated ATF4 expression promotes malignancy and gemcitabine resistance in pancreatic cancer via the TGF-β1/SMAD2/3 pathway and ABCC1 transactivation
title_full Cancer-associated fibroblasts-mediated ATF4 expression promotes malignancy and gemcitabine resistance in pancreatic cancer via the TGF-β1/SMAD2/3 pathway and ABCC1 transactivation
title_fullStr Cancer-associated fibroblasts-mediated ATF4 expression promotes malignancy and gemcitabine resistance in pancreatic cancer via the TGF-β1/SMAD2/3 pathway and ABCC1 transactivation
title_full_unstemmed Cancer-associated fibroblasts-mediated ATF4 expression promotes malignancy and gemcitabine resistance in pancreatic cancer via the TGF-β1/SMAD2/3 pathway and ABCC1 transactivation
title_short Cancer-associated fibroblasts-mediated ATF4 expression promotes malignancy and gemcitabine resistance in pancreatic cancer via the TGF-β1/SMAD2/3 pathway and ABCC1 transactivation
title_sort cancer-associated fibroblasts-mediated atf4 expression promotes malignancy and gemcitabine resistance in pancreatic cancer via the tgf-β1/smad2/3 pathway and abcc1 transactivation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8007632/
https://www.ncbi.nlm.nih.gov/pubmed/33782384
http://dx.doi.org/10.1038/s41419-021-03574-2
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