title: Isorhapontigenin (ISO) inhibited cell transformation by inducing G0/G1 phase arrest via increasing MKP-1 mRNA Stability.
abstract: The cancer chemopreventive property of Chinese herb new isolate isorhapontigenin (ISO) and mechanisms underlying its activity have never been explored. Here we demonstrated that ISO treatment with various concentrations for 3 weeks could dramatically inhibit TPA/EGF-induced cell transformation of Cl41 cells in Soft Agar assay, whereas co-incubation of cells with ISO at the same concentrations could elicit G0/G1 cell-cycle arrest without redundant cytotoxic effects on non-transformed cells. Further studies showed that ISO treatment resulted in cyclin D1 downregulation in dose- and time-dependent manner. Our results indicated that ISO regulated cyclin D1 at transcription level via targeting JNK/C-Jun/AP-1 activation. Moreover, we found that ISO-inhibited JNK/C-Jun/AP-1 activation was mediated by both upregulation of MKP-1 expression through increasing its mRNA stability and deactivating MKK7. Most importantly, MKP-1 knockdown could attenuate ISO-mediated suppression of JNK/C-Jun activation and cyclin D1 expression, as well as G0/G1 cell cycle arrest and cell transformation inhibition, while ectopic expression of FLAG-cyclin D1 T286A mutant also reversed ISO-induced G0/G1 cell-cycle arrest and inhibition of cell transformation. Our results demonstrated that ISO is a promising chemopreventive agent via upregulating mkp-1 mRNA stability, which is distinct from its cancer therapeutic effect with downregulation of XIAP and cyclin D1 expression.
authors.affiliation: Nelson Institute of Environmental Medicine, New York University School of Medicine,Tuxedo, NY, USA.
authors.forename: Guangxun
authors.initials: G
authors.lastname: Gao
authors.forename: Liang
authors.initials: L
authors.lastname: Chen
authors.forename: Jingxia
authors.initials: J
authors.lastname: Li
authors.forename: Dongyun
authors.initials: D
authors.lastname: Zhang
authors.forename: Yong
authors.initials: Y
authors.lastname: Fang
authors.forename: Haishan
authors.initials: H
authors.lastname: Huang
authors.forename: Xiequn
authors.initials: X
authors.lastname: Chen
authors.forename: Chuanshu
authors.initials: C
authors.lastname: Huang
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002448:Cell Adhesion / Q000187:drug effects; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects* / Q000473:pathology; D002478:Cells, Cultured; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D054638:Dual Specificity Phosphatase 1 / Q000235:genetics* / Q000378:metabolism; D004817:Epidermis / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D005434:Flow Cytometry; D016193:G1 Phase / Q000187:drug effects*; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D010766:Phosphorylation / Q000187:drug effects; D020871:RNA Stability / Q000187:drug effects* / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D016192:Resting Phase, Cell Cycle / Q000187:drug effects*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013267:Stilbenes / Q000494:pharmacology*
chemical_list: D012333:RNA, Messenger; D013267:Stilbenes; C432307:isorhapontigenin; D019938:Cyclin D1; D008156:Luciferases; D054638:Dual Specificity Phosphatase 1; C517020:Dusp1 protein, mouse