title: A phytoestrogen diarylheptanoid mediates estrogen receptor/Akt/glycogen synthase kinase 3β protein-dependent activation of the Wnt/β-catenin signaling pathway.
abstract: Estrogen promotes growth in many tissues by activating Wnt/β-catenin signaling. Recently, ASPP 049, a diarylheptanoid isolated from Curcuma comosa Roxb., has been identified as a phytoestrogen. This investigation determined the involvement of Wnt/β-catenin signaling in the estrogenic activity of this diarylheptanoid in transfected HEK 293T and in mouse preosteoblastic (MC3T3-E1) cells using a TOPflash luciferase assay and immunofluorescence. ASPP 049 rapidly activated T-cell-specific transcription factor/lymphoid enhancer binding factor-mediated transcription activity and induced β-catenin accumulation in the nucleus. Interestingly, the effects of ASPP 049 on the transcriptional activity and induction and accumulation of β-catenin protein in the nucleus of MC3T3-E1 cells were greater compared with estradiol. Activation of β-catenin in MC3T3-E1 cells was inhibited by ICI 182,780, suggesting that an estrogen receptor is required. In addition, ASPP 049 induced phosphorylations at serine 473 of Akt and serine 9 of GSK-3β. Moreover, ASPP 049 also induced proliferation and expressions of Wnt target genes Axin2 and Runx2 in MC3T3-E1 cells. In addition, ASPP 049 increased alkaline phosphatase expression, and activity that was abolished by DKK-1, a blocker of the Wnt/β-catenin receptor. Taken together, these results suggest that ASPP 049 from C. comosa induced osteoblastic cell proliferation and differentiation through ERα-, Akt-, and GSK-3β-dependent activation of β-catenin signaling. Our findings provide a scientific rationale for using C. comosa as a dietary supplement to prevent bone loss in postmenopausal women.
authors.affiliation: Department of Physiology, Faculty of Science, Mahidol University, Bangkok 10400, Thailand.
authors.forename: Kanit
authors.initials: K
authors.lastname: Bhukhai
authors.forename: Kanoknetr
authors.initials: K
authors.lastname: Suksen
authors.forename: Narumol
authors.initials: N
authors.lastname: Bhummaphan
authors.forename: Keatdamrong
authors.initials: K
authors.lastname: Janjorn
authors.forename: Natthakan
authors.initials: N
authors.lastname: Thongon
authors.forename: Duangrat
authors.initials: D
authors.lastname: Tantikanlayaporn
authors.forename: Pawinee
authors.initials: P
authors.lastname: Piyachaturawat
authors.forename: Apichart
authors.initials: A
authors.lastname: Suksamrarn
authors.forename: Arthit
authors.initials: A
authors.lastname: Chairoungdua
mesh_terms: D000818:Animals; D060466:Axin Protein / Q000235:genetics / Q000378:metabolism; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D050659:Core Binding Factor Alpha 1 Subunit / Q000235:genetics / Q000378:metabolism; D030024:Curcuma / Q000737:chemistry; D036381:Diarylheptanoids / Q000737:chemistry / Q000494:pharmacology*; D019587:Dietary Supplements; D004958:Estradiol / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D057809:HEK293 Cells; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism; D048789:Phytoestrogens / Q000737:chemistry / Q000494:pharmacology*; D017698:Postmenopause / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D060449:Wnt Signaling Pathway / Q000187:drug effects* / Q000502:physiology
chemical_list: C491761:AXIN2 protein, human; D060466:Axin Protein; C111729:Axin2 protein, mouse; D050659:Core Binding Factor Alpha 1 Subunit; C501126:DKK1 protein, human; D036381:Diarylheptanoids; C501127:Dkk1 protein, mouse; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D036341:Intercellular Signaling Peptides and Proteins; D048789:Phytoestrogens; C493709:RUNX2 protein, human; C493716:Runx2 protein, mouse; D004958:Estradiol; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3