title: Genistein-induced LKB1-AMPK activation inhibits senescence of VSMC through autophagy induction.
abstract: Genistein, the primary isoflavone from soy products, enhances antioxidant enzyme activities and inhibits tyrosine kinase. However, the mechanisms underlying genistein-induced autophagy are not yet completely understood. Autophagy refers to a regulated cellular process for the lysosomal-dependent turnover of organelles and proteins. During starvation or nutrient deficiency, autophagy provides an endogenous mechanism for prolonging survival. Here, we investigated whether genistein exerts autophagic effects through the activation of LKB1-AMPK signaling in VSMCs. Genistein dose- and time-dependently increased the phosphorylation of LKB1 and AMPK in VSMCs. LKB1 and AMPK induced autophagy through the downregulation of mTOR in VSMCs. Genistein-induced autophagy was inhibited in dominant-negative AMPK-transfected cells, whereas it was accelerated in cells transfected with the constitutively active form of AMPK. Increased autophagosome activity was confirmed by a concentration-dependent increase in LC3-II formation on Western blots and by increased perinuclear LC3-II puncta in genistein-treated VSMCs. Furthermore, genistein-induced autophagy attenuated adriamycin-induced SA-b-gal staining. These results suggest that genistein-dependent autophagy diminishes VSMC senescence and genistein may attenuate the VSMC senescence via an LKB1-AMPK-dependent mechanism.
authors.affiliation: Department of Pharmacology, College of Medicine, Yeungnam University, 170 Hyunchung-Ro, Daegu 42415, Republic of Korea; Smart-aging Convergence Research Center, College of Medicine, Yeungnam University, 170 Hyunchung-Ro, Daegu 42415, Republic of Korea.
authors.forename: Kyung Young
authors.initials: KY
authors.lastname: Lee
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, Yeungnam University, 170 Hyunchung-Ro, Daegu 42415, Republic of Korea; Smart-aging Convergence Research Center, College of Medicine, Yeungnam University, 170 Hyunchung-Ro, Daegu 42415, Republic of Korea.
authors.forename: Jae-Ryong
authors.initials: JR
authors.lastname: Kim
authors.affiliation: Department of Pharmacology, College of Medicine, Yeungnam University, 170 Hyunchung-Ro, Daegu 42415, Republic of Korea; Smart-aging Convergence Research Center, College of Medicine, Yeungnam University, 170 Hyunchung-Ro, Daegu 42415, Republic of Korea. Electronic address: hcchoi@med.yu.ac.kr.
authors.forename: Hyoung Chul
authors.initials: HC
authors.lastname: Choi
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000494:pharmacology; D004789:Enzyme Activation; D020536:Enzyme Activators / Q000494:pharmacology*; D019833:Genistein / Q000494:pharmacology*; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D006801:Humans; D018942:Macrolides / Q000494:pharmacology; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D034622:RNA Interference; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D013997:Time Factors; D014162:Transfection
chemical_list: D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases; D004317:Doxorubicin; D020536:Enzyme Activators; D019833:Genistein; D018942:Macrolides; D008869:Microtubule-Associated Proteins; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases; C526109:Anxa3 protein, rat; C057620:bafilomycin A; C546845:mTOR protein, rat; C488755:Stk11 protein, rat
keywords: AMPK; Autophagy; Genistein; LKB1; Senescence; Vascular smooth muscle cell (VSMC); mTOR