AMPK Inhibits the Stimulatory Effects of TGF-β on Smad2/3 Activity, Cell Migration, and Epithelial-to-Mesenchymal Transition.

Abstract

AMP-activated protein kinase (AMPK), an important downstream effector of the tumor suppressor liver kinase 1 (LKB1) and pharmacologic 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 transforming growth factor β (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 on the presence of LKB1. A similar effect was obtained by expressing a constitutive active mutant of AMPKα1 subunit, whereas the 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, TGF-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.

• Authors: Hui Lin, Nianshuang Li, Huan He, Ying Ying, Shashank Sunkara, Lingyu Luo, Nonghua Lv, Deqiang Huang, Zhijun Luo
• Journal: Molecular pharmacology (Mol Pharmacol) Vol. 88 Issue 6 Pg. 1062-71 (Dec 2015) ISSN: 1521-0111 [Electronic] United States
• PMID: 26424816 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.

Chemical References

• SMAD2 protein, human
• SMAD3 protein, human
• Smad2 Protein
• Smad3 Protein
• Transforming Growth Factor beta
• AMP-Activated Protein Kinases

Topics

• AMP-Activated Protein Kinases (metabolism)
• Animals
• Cell Line, Tumor
• Cell Movement (drug effects, physiology)
• Epithelial-Mesenchymal Transition (drug effects, physiology)
• Humans
• Mice
• Phosphorylation (drug effects, physiology)
• Smad2 Protein (antagonists & inhibitors, metabolism)
• Smad3 Protein (antagonists & inhibitors, metabolism)
• Transforming Growth Factor beta (antagonists & inhibitors, pharmacology)