TY - JOUR T1 - AMPK Inhibits the Stimulatory Effects of TGF-β on Smad2/3 Activity, Cell Migration and Epithelial to Mesenchymal Transition JF - Molecular Pharmacology JO - Mol Pharmacol DO - 10.1124/mol.115.099549 SP - mol.115.099549 AU - Hui Lin AU - Nianshuang Li AU - Huan He AU - Ying Ying AU - Shashank Sunkara AU - Lingyu Luo AU - Nonghua Lv AU - Deqiang Huang AU - Zhijun Luo Y1 - 2015/01/01 UR - http://molpharm.aspetjournals.org/content/early/2015/09/30/mol.115.099549.abstract N2 - AMP-activated protein kinase (AMPK), an important downstream effector of the tumor suppressor LKB1 and pharmacological target of metformin, is well-known to exert a preventive and inhibitory effect on tumorigenesis. However, its role in cancer progression and metastasis has not been well characterized. The present study investigates the potential roles of AMPK in inhibiting cancer cell migration and epithelial-to-mesenchymal transition (EMT) by regulating the canonical TGF-β signaling pathway, an important promoting factor for cancer progression. Our results showed that activation of AMPK by metformin inhibited TGF-β-induced Smad2/3 phosphorylation in cancer cells in a dose-dependent manner. The effect of metformin is dependent upon the presence of LKB1. A similar effect was obtained by expressing a constitutive active mutant of AMPKα1 subunit, whereas expression of a dominant negative mutant of AMPKα1 or ablation of AMPKα subunits greatly enhanced TGF-β stimulation of Smad2/3 phosphorylation. As a consequence, expression of genes downstream of Smad2/3, including plasminogen activator inhibitor-1, fibronectin, and connective tissue growth factor, was suppressed by metformin in a LKB1-dependent fashion. In addition, metformin blocked TGF-β-induced inteleukin-6 expression through both LKB1-dependent and independent mechanisms. Our results also indicate that activation of LKB1/AMPK inhibits TGF-β-stimulated cancer cell migration. Finally, β induction of EMT was inhibited by phenformin and enhanced by knockdown of LKB1 expression with shRNA. Together, our data suggest that AMPK could be a drug target for controlling cancer progression and metastasis. ER -