Lovastatin Inhibits EMT and Metastasis of Triple-Negative Breast Cancer Stem Cells Through Dysregulation of Cytoskeleton-Associated Proteins.
Lovastatin Inhibits EMT and Metastasis of Triple-Negative Breast Cancer Stem Cells Through Dysregulation of Cytoskeleton-Associated Proteins.
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洛伐他汀通过细胞骨架相关蛋白失调抑制三阴性乳腺癌干细胞的 EMT 和转移
DOI：
10.3389/fonc.2021.656687
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发表时间：
2021
影响因子：
4.7
通讯作者：
Deng X
中科院分区：
文献类型：
--
作者：
Zheng C;Yan S;Lu L;Yao H;He G;Chen S;Li Y;Peng X;Cheng Z;Wu M;Zhang Q;Li G;Fu S;Deng X
与其他亚型乳腺癌相比，三阴性乳腺癌（TNBC）更具侵袭性，预后较差。上皮-间充质转化（epithelial -to-mesenchymal transition， EMT）是上皮细胞向间充质样细胞转化的过程，具有迁移、侵袭和转移的能力。最近，我们已经证明洛伐他汀是一种3-羟基-3-甲基戊二酰辅酶a还原酶抑制剂和降脂药物，可以在体外和体内抑制来自TNBC细胞的癌症干细胞（CSCs）的干细胞特性。本研究旨在探讨洛伐他汀是否通过抑制EMT和抑制转移来抑制TNBC CSCs及其机制。在本研究中，我们发现洛伐他汀在TNBC MDA-MB-231细胞来源的CSCs中失调细胞骨架相关蛋白的赖氨酸琥珀酰化。洛伐他汀通过下调MDA-MB-231 CSCs中Vimentin和Twist的蛋白水平以及逆转TGF-β1诱导的MCF10A细胞的形态学改变来抑制EMT。洛伐他汀也抑制MDA-MB-231 CSCs的迁移。洛伐他汀对TNBC CSCs细胞骨架的破坏表现为假足数量的减少和f -肌动蛋白细胞骨架的重新定位。洛伐他汀联合阿霉素协同抑制MDA-MB-231 CSCs肝转移。生物信息学分析显示，细胞骨架相关基因的高表达水平是TNBC的特征，并预测了乳腺癌患者的生存结果。这些数据表明洛伐他汀可以通过细胞骨架相关蛋白的失调抑制TNBC CSCs的体外和体内EMT和转移。
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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影响因子：
45.3
作者：
Liu, Suling;Wicha, Max S.
通讯作者：
Wicha, Max S.
影响因子：
2.3
作者：
Lee S
通讯作者：
Lee S
DOI：
10.1158/1078-0432.ccr-09-2937
发表时间：
2010-05-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Li Y;Zhang T;Korkaya H;Liu S;Lee HF;Newman B;Yu Y;Clouthier SG;Schwartz SJ;Wicha MS;Sun D
通讯作者：
Sun D
影响因子：
4.6
作者：
Li QQ;Hao JJ;Zhang Z;Krane LS;Hammerich KH;Sanford T;Trepel JB;Neckers L;Agarwal PK
通讯作者：
Agarwal PK
影响因子：
3.9
作者：
Peng Y;He G;Tang D;Xiong L;Wen Y;Miao X;Hong Z;Yao H;Chen C;Yan S;Lu L;Yang Y;Li Q;Deng X
通讯作者：
Deng X