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Lovastatin Inhibits EMT and Metastasis of Triple-Negative Breast Cancer Stem Cells Through Dysregulation of Cytoskeleton-Associated Proteins

Triple-negative breast cancer (TNBC) is more aggressive and has poorer prognosis compared to other subtypes of breast cancer. Epithelial-to-mesenchymal transition (EMT) is a process in which epithelial cells transform into mesenchymal-like cells capable of migration, invasion, and metastasis. Recent...

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Autores principales: Zheng, Chanjuan, Yan, Shichao, Lu, Lu, Yao, Hui, He, Guangchun, Chen, Sisi, Li, Ying, Peng, Xiaojun, Cheng, Zhongyi, Wu, Mi, Zhang, Qiuting, Li, Guifei, Fu, Shujun, Deng, Xiyun
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8212055/
https://www.ncbi.nlm.nih.gov/pubmed/34150623
http://dx.doi.org/10.3389/fonc.2021.656687
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author Zheng, Chanjuan
Yan, Shichao
Lu, Lu
Yao, Hui
He, Guangchun
Chen, Sisi
Li, Ying
Peng, Xiaojun
Cheng, Zhongyi
Wu, Mi
Zhang, Qiuting
Li, Guifei
Fu, Shujun
Deng, Xiyun
author_facet Zheng, Chanjuan
Yan, Shichao
Lu, Lu
Yao, Hui
He, Guangchun
Chen, Sisi
Li, Ying
Peng, Xiaojun
Cheng, Zhongyi
Wu, Mi
Zhang, Qiuting
Li, Guifei
Fu, Shujun
Deng, Xiyun
author_sort Zheng, Chanjuan
collection PubMed
description Triple-negative breast cancer (TNBC) is more aggressive and has poorer prognosis compared to other subtypes of breast cancer. Epithelial-to-mesenchymal transition (EMT) is a process in which epithelial cells transform into mesenchymal-like cells capable of migration, invasion, and metastasis. Recently, we have demonstrated that lovastatin, a 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor and a lipid-lowering drug, could inhibit stemness properties of cancer stem cells (CSCs) derived from TNBC cell in vitro and in vivo. This study is aimed at investigating whether lovastatin inhibits TNBC CSCs by inhibiting EMT and suppressing metastasis and the mechanism involved. In the present study, we found that lovastatin dysregulated lysine succinylation of cytoskeleton-associated proteins in CSCs derived from TNBC MDA-MB-231 cell. Lovastatin inhibited EMT as demonstrated by down-regulation of the protein levels of Vimentin and Twist in MDA-MB-231 CSCs in vitro and vivo and by reversal of TGF-β1-induced morphological change in MCF10A cells. Lovastatin also inhibited the migration of MDA-MB-231 CSCs. The disruption of cytoskeleton in TNBC CSCs by lovastatin was demonstrated by the reduction of the number of pseudopodia and the relocation of F-actin cytoskeleton. Combination of lovastatin with doxorubicin synergistically inhibited liver metastasis of MDA-MB-231 CSCs. Bioinformatics analysis revealed that higher expression levels of cytoskeleton-associated genes were characteristic of TNBC and predicted survival outcomes in breast cancer patients. These data suggested that lovastatin could inhibit the EMT and metastasis of TNBC CSCs in vitro and in vivo through dysregulation of cytoskeleton-associated proteins.
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spelling pubmed-82120552021-06-19 Lovastatin Inhibits EMT and Metastasis of Triple-Negative Breast Cancer Stem Cells Through Dysregulation of Cytoskeleton-Associated Proteins Zheng, Chanjuan Yan, Shichao Lu, Lu Yao, Hui He, Guangchun Chen, Sisi Li, Ying Peng, Xiaojun Cheng, Zhongyi Wu, Mi Zhang, Qiuting Li, Guifei Fu, Shujun Deng, Xiyun Front Oncol Oncology Triple-negative breast cancer (TNBC) is more aggressive and has poorer prognosis compared to other subtypes of breast cancer. Epithelial-to-mesenchymal transition (EMT) is a process in which epithelial cells transform into mesenchymal-like cells capable of migration, invasion, and metastasis. Recently, we have demonstrated that lovastatin, a 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor and a lipid-lowering drug, could inhibit stemness properties of cancer stem cells (CSCs) derived from TNBC cell in vitro and in vivo. This study is aimed at investigating whether lovastatin inhibits TNBC CSCs by inhibiting EMT and suppressing metastasis and the mechanism involved. In the present study, we found that lovastatin dysregulated lysine succinylation of cytoskeleton-associated proteins in CSCs derived from TNBC MDA-MB-231 cell. Lovastatin inhibited EMT as demonstrated by down-regulation of the protein levels of Vimentin and Twist in MDA-MB-231 CSCs in vitro and vivo and by reversal of TGF-β1-induced morphological change in MCF10A cells. Lovastatin also inhibited the migration of MDA-MB-231 CSCs. The disruption of cytoskeleton in TNBC CSCs by lovastatin was demonstrated by the reduction of the number of pseudopodia and the relocation of F-actin cytoskeleton. Combination of lovastatin with doxorubicin synergistically inhibited liver metastasis of MDA-MB-231 CSCs. Bioinformatics analysis revealed that higher expression levels of cytoskeleton-associated genes were characteristic of TNBC and predicted survival outcomes in breast cancer patients. These data suggested that lovastatin could inhibit the EMT and metastasis of TNBC CSCs in vitro and in vivo through dysregulation of cytoskeleton-associated proteins. Frontiers Media S.A. 2021-06-04 /pmc/articles/PMC8212055/ /pubmed/34150623 http://dx.doi.org/10.3389/fonc.2021.656687 Text en Copyright © 2021 Zheng, Yan, Lu, Yao, He, Chen, Li, Peng, Cheng, Wu, Zhang, Li, Fu and Deng https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Oncology
Zheng, Chanjuan
Yan, Shichao
Lu, Lu
Yao, Hui
He, Guangchun
Chen, Sisi
Li, Ying
Peng, Xiaojun
Cheng, Zhongyi
Wu, Mi
Zhang, Qiuting
Li, Guifei
Fu, Shujun
Deng, Xiyun
Lovastatin Inhibits EMT and Metastasis of Triple-Negative Breast Cancer Stem Cells Through Dysregulation of Cytoskeleton-Associated Proteins
title Lovastatin Inhibits EMT and Metastasis of Triple-Negative Breast Cancer Stem Cells Through Dysregulation of Cytoskeleton-Associated Proteins
title_full Lovastatin Inhibits EMT and Metastasis of Triple-Negative Breast Cancer Stem Cells Through Dysregulation of Cytoskeleton-Associated Proteins
title_fullStr Lovastatin Inhibits EMT and Metastasis of Triple-Negative Breast Cancer Stem Cells Through Dysregulation of Cytoskeleton-Associated Proteins
title_full_unstemmed Lovastatin Inhibits EMT and Metastasis of Triple-Negative Breast Cancer Stem Cells Through Dysregulation of Cytoskeleton-Associated Proteins
title_short Lovastatin Inhibits EMT and Metastasis of Triple-Negative Breast Cancer Stem Cells Through Dysregulation of Cytoskeleton-Associated Proteins
title_sort lovastatin inhibits emt and metastasis of triple-negative breast cancer stem cells through dysregulation of cytoskeleton-associated proteins
topic Oncology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8212055/
https://www.ncbi.nlm.nih.gov/pubmed/34150623
http://dx.doi.org/10.3389/fonc.2021.656687
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