title: 20-O-β-D-glucopyranosyl-20(S)-protopanaxadiol suppresses UV-Induced MMP-1 expression through AMPK-mediated mTOR inhibition as a downstream of the PKA-LKB1 pathway.
abstract: Various health effects have been attributed to the ginsenoside metabolite 20-O-β-D-glucopyranosyl-20(S)-protopanaxadiol (GPD); however, its effect on ultraviolet (UV)-induced matrix metalloproteinase (MMP)-1 expression and the mechanism underlying this effect are unknown. We examined the inhibitory effect of GPD on UV-induced MMP-1 expression and its mechanisms in human dermal fibroblasts (HDFs). GPD attenuated UV-induced MMP-1 expression in HDFs and suppressed the UV-induced phosphorylation of mammalian target of rapamycin (mTOR) and p70(S6K) without inhibiting the activity of phosphatidylinositol 3-kinase and Akt, which are well-known upstream kinases of mTOR. GPD augmented the phosphorylation of liver kinase B1 (LKB1) and adenosine monophosphate-activated protein kinase (AMPK), which are inhibitors of mTOR, to a greater extent than UV treatment alone. Similar to GPD, 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranosyl 5'-monophosphate (AICAR), an activator of AMPK, augmented UV-induced AMPK phosphorylation to a greater extent than UV treatment alone, resulting in the inhibition of MMP-1 expression. AICAR also decreased the phosphorylation of mTOR and p70(S6K). However, compound C, an antagonist of AMPK, increased MMP-1 expression. In HDF cells with AMPK knock-down using shRNA, MMP-1 expression was increased. These results indicate that AMPK activation plays a key role in MMP-1 suppression. Additionally, the cAMP-dependent protein kinase (PKA) inhibitor, H-89, antagonized GPD-mediated MMP-1 suppression via the inhibition of LKB1. Our results suggest that the suppressive activity of GPD on UV-induced MMP-1 expression is due to the activation of AMPK as a downstream of the PKA-LKB1 pathway.
authors.affiliation: WCU Biomodulation Major, Department of Agricultural Biotechnology and Center for Food and Bioconvergence, Seoul National University, Seoul, 151-921, Republic of Korea.
authors.forename: Dong Joo
authors.initials: DJ
authors.lastname: Shin
authors.forename: Jong-Eun
authors.initials: JE
authors.lastname: Kim
authors.forename: Tae-Gyu
authors.initials: TG
authors.lastname: Lim
authors.forename: Eun Hee
authors.initials: EH
authors.lastname: Jeong
authors.forename: Gaeun
authors.initials: G
authors.lastname: Park
authors.forename: Nam Joo
authors.initials: NJ
authors.lastname: Kang
authors.forename: Jun-Seong
authors.initials: JS
authors.lastname: Park
authors.forename: Myeong-Hun
authors.initials: MH
authors.lastname: Yeom
authors.forename: Deok Kun
authors.initials: DK
authors.lastname: Oh
authors.forename: Ann M
authors.initials: AM
authors.lastname: Bode
authors.forename: Zigang
authors.initials: Z
authors.lastname: Dong
authors.forename: Hyong Joo
authors.initials: HJ
authors.lastname: Lee
authors.forename: Ki Won
authors.initials: KW
authors.lastname: Lee
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases / Q000096:biosynthesis* / Q000235:genetics; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000494:pharmacology; D002460:Cell Line; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D005347:Fibroblasts; D036145:Ginsenosides / Q000494:pharmacology*; D006801:Humans; D007546:Isoquinolines / Q000494:pharmacology; D020781:Matrix Metalloproteinase 1 / Q000096:biosynthesis*; D010078:Oxazines / Q000494:pharmacology; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering; D012265:Ribonucleotides / Q000494:pharmacology; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000037:antagonists & inhibitors; D013449:Sulfonamides / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D014466:Ultraviolet Rays
chemical_list: D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases; D000620:Aminoimidazole Carboxamide; D017868:Cyclic AMP-Dependent Protein Kinases; D036145:Ginsenosides; D007546:Isoquinolines; D020781:Matrix Metalloproteinase 1; D010078:Oxazines; D058539:Phosphatidylinositol 3-Kinase; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D034741:RNA, Small Interfering; D012265:Ribonucleotides; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D013449:Sulfonamides; D058570:TOR Serine-Threonine Kinases; C085142:oxadin; C112772:ginsenoside compound K; C546842:MTOR protein, human; C109790:STK11 protein, human; C031143:AICA ribonucleotide; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide
keywords: 20-O-β-D-GLUCOPYRANOSYL-20(S)-PROTOPANAXADIOL; AMPK; GINSENOSIDES; MMP-1; SKIN AGING; UV; mTOR