Metformin Sensitizes Non-small Cell Lung Cancer Cells to an Epigallocatechin-3-Gallate (EGCG) Treatment by Suppressing the Nrf2/HO-1 Signaling Pathway.
Metformin Sensitizes Non-small Cell Lung Cancer Cells to an Epigallocatechin-3-Gallate (EGCG) Treatment by Suppressing the Nrf2/HO-1 Signaling Pathway.
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二甲双胍通过抑制 Nrf2/HO-1 信号通路使非小细胞肺癌细胞对表没食子儿茶素-3-没食子酸酯 (EGCG) 治疗敏感
DOI：
10.7150/ijbs.18830
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发表时间：
2017
影响因子：
9.2
通讯作者：
Cao J
中科院分区：
文献类型：
--
作者：
Yu C;Jiao Y;Xue J;Zhang Q;Yang H;Xing L;Chen G;Wu J;Zhang S;Zhu W;Cao J
非小细胞肺癌（NSCLC）是最常见的肺癌类型。（-）-表没食子儿茶素-3-没食子酸酯（EGCG）是绿色茶中的一种主要多酚，被广泛研究作为具有潜在抗癌作用的癌症化学预防剂。NF-E2相关因子2（Nrf 2）/血红素加氧酶-1（HO-1）信号通路被认为介导细胞对EGCG的抗性。二甲双胍是一种经典的抗糖尿病药物，已被证明可以预防癌症进展。研究人员尚未报道二甲双胍是否增强EGCG的抗癌功效。在这项研究中，二甲双胍抑制HO-1的表达，增强了EGCG的抗肿瘤作用。二甲双胍还增强了EGCG（100 μM）诱导的ROS（活性氧）生成，随后导致细胞凋亡。基于体内研究的结果，用二甲双胍和EGCG的组合处理的异种移植物的尺寸小于其他组。二甲双胍通过Nrf 2的Sirtuin 1（SIRT 1）依赖性脱乙酰化作用调节EGCG激活的Nrf 2/HO-1通路。此外，二甲双胍上调SIRT 1表达部分通过NF-κ B途径。相比之下，EGCG和二甲双胍的组合对正常肺上皮BEAS-2B细胞的影响很小。基于我们的发现，二甲双胍通过抑制Nrf 2/HO-1信号通路使NSCLC细胞对EGCG治疗敏感。
Non-small cell lung cancer (NSCLC) is the most common type of lung cancer. (-)-Epigallocatechin-3-gallate (EGCG), a major polyphenol in green tea, is widely studied as a cancer chemopreventive agent with potential anti-cancer effects. The NF-E2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) signaling pathway is considered to mediate cellular resistance to EGCG. Metformin, a classical antidiabetic drug, has been shown to prevent cancer progression. Researchers have not reported whether metformin potentiates the anti-cancer efficacy of EGCG. In this study, metformin inhibited HO-1 expression and augmented the anti-tumor effect of EGCG. Metformin also enhanced ROS (reactive oxygen species) generation induced by EGCG (100 μM), subsequently resulting in apoptosis. Based on the results of the in vivo study, size of xenografts treated with the combination of metformin and EGCG was smaller than other groups. Mechanistically, metformin modulated the EGCG-activated Nrf2/HO-1 pathway through Sirtuin 1 (SIRT1)-dependent deacetylation of Nrf2. Moreover, metformin upregulated SIRT1 expression partially through the NF-kB pathway. Comparatively, the combination of EGCG and metformin showed little impact on normal lung epithelial BEAS-2B cells. Based on our findings, metformin sensitized NSCLC cells to the EGCG treatment by suppressing the Nrf2/HO-1 signaling pathway.
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