Metformin exhibited anticancer activity by lowering cellular cholesterol content in breast cancer cells
Metformin exhibited anticancer activity by lowering cellular cholesterol content in breast cancer cells
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DOI：
10.1371/journal.pone.0209435
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发表时间：
2019-01-09
期刊：
影响因子：
3.7
通讯作者：
Mandal, Chandi C.
中科院分区：
文献类型：
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作者：
Sharma, Ankit;Bandyopadhayaya, Shreetama;Mandal, Chandi C.
二甲双胍是一种广泛使用的抗糖尿病药物，在各种癌症类型中显示出抗癌活性。很少有研究证明二甲双胍使用者血清中LDL和总胆固醇水平降低。基于这些观点，本研究旨在确定二甲双胍是否通过降低癌细胞中的胆固醇水平而表现出抗癌活性。本研究发现，用二甲双胍处理乳腺癌MDA-MB-231细胞显著降低胆固醇含量，同时抑制各种胆固醇调节基因（例如，HMGCoR、LDLR和SREBP 1）。二甲双胍降低了转移性MDA-MB-231细胞的细胞活力、迁移和干性。同样，二甲双胍治疗抑制了抗凋亡基因BCL 2和Bcl-xL以及间充质基因波形蛋白、N-钙粘蛋白、Zeb1和Zeb2的表达，同时增强了凋亡半胱氨酸蛋白酶3和Bax以及上皮基因E-钙粘蛋白和角蛋白19的表达，证实了二甲双胍在肿瘤发生中的抑制作用。与二甲双胍类似，甲基β环糊精（MBCD）消耗胆固醇可降低乳腺癌细胞的细胞活力、迁移、EMT和干性。此外，二甲双胍抑制的细胞活力，迁移，集落和球体形成逆转胆固醇治疗。类似地，胆固醇处理逆转二甲双胍减少了几种基因表达（例如，Bcl-xL、BCL 2、Zeb1、波形蛋白和BMI-1）。此外，酶谱数据表明，胆固醇上调二甲双胍抑制MMP活性。这些结果表明，二甲双胍通过降低乳腺癌细胞中的胆固醇含量而显示出抗癌活性。因此，这项研究首次揭示了二甲双胍介导的抗癌活性的这种额外机制。
Metformin, a widely prescribed anti-diabetic drug, shows anticancer activity in various cancer types. Few studies documented that there was a decreased level of LDL and total cholesterol in blood serum of metformin users. Based on these views, this study aimed to determine if metformin exhibits anticancer activity by alleviating cholesterol level in cancer cells. The present study found that treatment of breast cancer MDA-MB-231 cells with metformin significantly decreased cholesterol content with concomitant inhibition of various cholesterol regulatory genes (e.g., HMGCoR, LDLR and SREBP1). Metformin decreased cell viability, migration and stemness in metastatic MDA-MB-231 cells. Similarly, metformin treatment suppressed expressions of anti-apoptotic genes BCL2 and Bcl-xL, and mesenchymal genes vimentin, N-cadherin, Zeb1 and Zeb2 with simultaneous enhancement of apoptotic caspase 3 and Bax, and epithelial genes E-cadherin and keratin 19 expressions, confirming an inhibitory effect of metformin in tumorigenesis. Similar to metformin, depletion of cholesterol by methyl beta cyclodextrin (MBCD) diminished cell viability, migration, EMT and stemness in breast cancer cells. Moreover, metformin-inhibited cell viability, migration, colony and sphere formations were reversed back by cholesterol treatment. Similarly, cholesterol treatment inverted metformin-reduced several gene expressions (e.g., Bcl-xL, BCL2, Zeb1, vimentin, and BMI-1). Additionally, zymography data demonstrated that cholesterol upregulated metformin-suppressed MMP activity. These findings suggested that metformin revealed anticancer activity by lowering of cholesterol content in breast cancer cells. Thus, this study, for the first time, unravelled this additional mechanism of metformin-mediated anticancer activity.