LKB1/AMPK inhibits TGF-β1 production and the TGF-β signaling pathway in breast cancer cells.
LKB1/AMPK inhibits TGF-β1 production and the TGF-β signaling pathway in breast cancer cells.
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LKB1/AMPK 抑制乳腺癌细胞中 TGF-β 1 的产生和 TGF-β 信号通路
DOI：
10.1007/s13277-015-4639-9
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发表时间：
2016-06
期刊：
影响因子：
--
通讯作者：
Luo Z
中科院分区：
文献类型：
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作者：
Li NS;Zou JR;Lin H;Ke R;He XL;Xiao L;Huang D;Luo L;Lv N;Luo Z
腺苷单磷酸活化蛋白激酶（AMPK）作为维持正常细胞和癌细胞能量稳态的燃料计，已经成为一种肿瘤抑制因子。本研究旨在阐明AMPK与转化生长因子β (TGF-β)之间的功能关系。结果表明，AMPK上游激酶肝激酶B1 （LKB1）的表达可抑制TGF-β诱导的乳腺癌细胞Smad磷酸化及其转录活性，而短发夹RNA （shRNA）敲低LKB1或AMPKα1亚基可增强TGF-β的作用。此外，AMPK的激活降低了TGF-β1的启动子活性。因此，与未服用二甲双胍的2型糖尿病患者相比，服用二甲双胍的2型糖尿病患者血清TGF-β1有降低的趋势。二甲双胍治疗后小鼠血清TGF-β1明显降低。这些结果表明AMPK抑制TGF-β1的转录，导致其在血清中的浓度降低。最后，二甲双胍抑制乳腺上皮细胞向间质转化。综上所述，我们的研究表明AMPK对TGF-β信号具有多种作用，并支持AMPK可作为乳腺癌的治疗药物靶点。
Adenosine monophosphate-activated protein kinase (AMPK) acts as a fuel gauge that maintains energy homeostasis in both normal and cancerous cells, and has emerged as a tumor suppressor. The present study aims to delineate the functional relationship between AMPK and transforming growth factor beta (TGF-β). Our results showed that expression of liver kinase B1 (LKB1), an upstream kinase of AMPK, impeded TGF-β-induced Smad phosphorylation and their transcriptional activity in breast cancer cells, whereas knockdown of LKB1 or AMPKα1 subunit by short hairpin RNA (shRNA) enhanced the effect of TGF-β. Furthermore, AMPK activation reduced the promoter activity of TGF-β1. In accordance, type 2 diabetic patients taking metformin displayed a trend of reduction of serum TGF-β1, as compared with those without metformin. A significant reduction of serum TGF-β1 was found in mice after treatment with metformin. These results suggest that AMPK inhibits the transcription of TGF-β1, leading to reduction of its concentration in serum. Finally, metformin suppressed epithelial-to-mesenchymal transition of mammary epithelial cells. Taken together, our study demonstrates that AMPK exerts multiple actions on TGF-β signaling and supports that AMPK can serve as a therapeutic drug target for breast cancer.