title: LKB1/AMPK inhibits TGF-β1 production and the TGF-β signaling pathway in breast cancer cells.
abstract: 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.
authors.affiliation: Research Institute of Digestive Diseases and Department of Gastroenterology, The First Affiliated Hospital, Nanchang University, Nanchang, Jiangxi, China.|Graduate Program of Basic Medical Sciences, School of Basic Medical Sciences, Nanchang University, Nanchang, Jiangxi, China.
authors.forename: Nian-Shuang
authors.initials: NS
authors.lastname: Li
authors.affiliation: Research Institute of Digestive Diseases and Department of Gastroenterology, The First Affiliated Hospital, Nanchang University, Nanchang, Jiangxi, China.
authors.forename: Jun-Rong
authors.initials: JR
authors.lastname: Zou
authors.affiliation: Graduate Program of Basic Medical Sciences, School of Basic Medical Sciences, Nanchang University, Nanchang, Jiangxi, China.|Department of Biochemistry, Boston University School of Medicine, 72 East Concord Street, Boston, MA, 02118, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Lin
authors.affiliation: Graduate Program of Basic Medical Sciences, School of Basic Medical Sciences, Nanchang University, Nanchang, Jiangxi, China.
authors.forename: Rong
authors.initials: R
authors.lastname: Ke
authors.affiliation: Graduate Program of Basic Medical Sciences, School of Basic Medical Sciences, Nanchang University, Nanchang, Jiangxi, China.
authors.forename: Xiao-Ling
authors.initials: XL
authors.lastname: He
authors.affiliation: Graduate Program of Basic Medical Sciences, School of Basic Medical Sciences, Nanchang University, Nanchang, Jiangxi, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Xiao
authors.affiliation: Research Institute of Digestive Diseases and Department of Gastroenterology, The First Affiliated Hospital, Nanchang University, Nanchang, Jiangxi, China.
authors.forename: Deqiang
authors.initials: D
authors.lastname: Huang
authors.affiliation: Research Institute of Digestive Diseases and Department of Gastroenterology, The First Affiliated Hospital, Nanchang University, Nanchang, Jiangxi, China.
authors.forename: Lingyu
authors.initials: L
authors.lastname: Luo
authors.affiliation: Research Institute of Digestive Diseases and Department of Gastroenterology, The First Affiliated Hospital, Nanchang University, Nanchang, Jiangxi, China. lunonghua@ncu.edu.cn.
authors.forename: Nonghua
authors.initials: N
authors.lastname: Lv
authors.affiliation: Graduate Program of Basic Medical Sciences, School of Basic Medical Sciences, Nanchang University, Nanchang, Jiangxi, China. zluo@bu.edu.|Department of Biochemistry, Boston University School of Medicine, 72 East Concord Street, Boston, MA, 02118, USA. zluo@bu.edu.
authors.forename: Zhijun
authors.initials: Z
authors.lastname: Luo
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases / Q000235:genetics*; D000368:Aged; D000818:Animals; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects / Q000235:genetics; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D008297:Male; D008687:Metformin / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008875:Middle Aged; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D034741:RNA, Small Interfering; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D014945:Wound Healing
chemical_list: D007004:Hypoglycemic Agents; D034741:RNA, Small Interfering; D053773:Transforming Growth Factor beta1; D008687:Metformin; D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases
keywords: AMPK; Breast cancer cell migration; Epithelial-to-mesenchymal transition; LKB1; TGF-β production and signaling