Combined treatment with troglitazone and lovastatin inhibited epidermal growth factor-induced migration through the downregulation of cysteine-rich protein 61 in human anaplastic thyroid cancer cells.
Combined treatment with troglitazone and lovastatin inhibited epidermal growth factor-induced migration through the downregulation of cysteine-rich protein 61 in human anaplastic thyroid cancer cells.
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DOI：
10.1371/journal.pone.0118674
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Liang YC
中科院分区：
文献类型：
--
作者：
Chin LH;Hsu SP;Zhong WB;Liang YC
我们的前期研究表明表皮生长因子（EGF）可以通过诱导人甲状腺未分化癌（ATC）细胞中富含半胱氨酸的蛋白61（Cyr 61）来诱导细胞迁移。本研究的目的是确定在临床可达到的浓度下，过氧化物酶体增殖物激活受体-γ（PPARγ）配体曲格列酮和降胆固醇药物洛伐他汀联合治疗对ATC细胞迁移的抑制作用。5 μM曲格列酮和1 μM洛伐他汀的联合治疗没有显示出细胞毒性，但显著抑制EGF诱导的迁移，如使用伤口愈合和Boyden室试验所确定的。曲格列酮和洛伐他汀的共同治疗改变了上皮-间质转化（EMT）相关标志物基因的细胞表达，特别是，E-cadherin表达增加，波形蛋白表达减少。此外，共处理减少了被认为参与迁移的丝状伪足的数量，并显著抑制EGF诱导的Cyr 61 mRNA和蛋白表达以及Cyr 61分泌。此外，在曲格列酮和洛伐他汀共同处理的细胞中，EGF诱导Cyr 61表达的2个关键信号分子，cAMP反应元件结合蛋白（CREB）和细胞外信号调节激酶（ERK）的磷酸化水平降低。进行瞬时转染试验表明，联合治疗显着抑制Cyr 61启动子活性。这些结果表明，低剂量曲格列酮和洛伐他汀联合治疗可有效抑制ATC细胞迁移，并可作为转移性ATC的一种新的治疗策略。
Our previous studies have demonstrated that epidermal growth factor (EGF) can induce cell migration through the induction of cysteine-rich protein 61 (Cyr61) in human anaplastic thyroid cancer (ATC) cells. The aim of the present study was to determine the inhibitory effects of combined treatment with the peroxisome proliferator-activated receptor-γ (PPARγ) ligand troglitazone and the cholesterol-lowering drug lovastatin at clinically achievable concentrations on ATC cell migration. Combined treatment with 5 μM troglitazone and 1 μM lovastatin exhibited no cytotoxicity but significantly inhibited EGF-induced migration, as determined using wound healing and Boyden chamber assays. Cotreatment with troglitazone and lovastatin altered the epithelial-to-mesenchymal-transition (EMT) -related marker gene expression of the cells; specifically, E-cadherin expression increased and vimentin expression decreased. In addition, cotreatment reduced the number of filopodia, which are believed to be involved in migration, and significantly inhibited EGF-induced Cyr61 mRNA and protein expression as well as Cyr61 secretion. Moreover, the phosphorylation levels of 2 crucial signal molecules for EGF-induced Cyr61 expression, the cAMP response element-binding protein (CREB) and extracellular signal-regulated kinase (ERK), were decreased in cells cotreated with troglitazone and lovastatin. Performing a transient transfection assay revealed that the combined treatment significantly suppressed Cyr61 promoter activity. These results suggest that combined treatment with low doses of troglitazone and lovastatin effectively inhibits ATC cell migration and may serve as a novel therapeutic strategy for metastatic ATC.
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影响因子：
1.9
作者：
Guerra A;Di Crescenzo V;Garzi A;Cinelli M;Carlomagno C;Tonacchera M;Zeppa P;Vitale M
通讯作者：
Vitale M
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影响因子：
37.3
作者：
Kunz, Manfred;Ibrahim, Saleh M
通讯作者：
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影响因子：
2.9
作者：
Bolden A;Bernard L;Jones D;Akinyeke T;Stewart LV
通讯作者：
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DOI：
10.1073/pnas.95.11.6355
发表时间：
1998-05-26
影响因子：
11.1
作者：
Babic, AM;Kireeva, ML;Lau, LF
通讯作者：
Lau, LF
影响因子：
5.2
作者：
Lin, Been-Ren;Chang, Cheng-Chi;Lin, Ming-Tsan
通讯作者：
Lin, Ming-Tsan