LKB1/AMPK inhibits TGF-β1 production and the TGF-β signaling pathway in breast cancer cells

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-beta). Our results showed that expression of liver kinase B1 (LKB1), an upstream kinase of AMPK, impeded TGF-beta-induced Smad phosphorylation and their transcriptional activity in breast cancer cells, whereas knockdown of LKB1 or AMPK alpha 1 subunit by short hairpin RNA (shRNA) enhanced the effect of TGF-beta. Furthermore, AMPK activation reduced the promoter activity of TGF-beta 1. In accordance, type 2 diabetic patients taking metformin displayed a trend of reduction of serum TGF-beta 1, as compared with those without metformin. A significant reduction of serum TGF-beta 1 was found in mice after treatment with metformin. These results suggest that AMPK inhibits the transcription of TGF-beta 1, 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-beta signaling and supports that AMPK can serve as a therapeutic drug target for breast cancer.