title: Jaceosidin, isolated from dietary mugwort (Artemisia princeps), induces G2/M cell cycle arrest by inactivating cdc25C-cdc2 via ATM-Chk1/2 activation.
abstract: Jaceosidin, a flavonoid derived from Artemisia princeps (Japanese mugwort), has been shown to inhibit the growth of several human cancer cells, However, the exact mechanism for the cytotoxic effect of jaceosidin is not completely understood. In this study, we investigated the molecular mechanism involved in the antiproliferative effect of jaceosidin in human endometrial cancer cells. We demonstrated that jaceosidin is a more potent inhibitor of cell growth than cisplatin in human endometrial cancer cells. In contrast, jaceosidin-induced cytotoxicity in normal endometrial cells was lower than that observed for cisplatin. Jaceosidin induced G2/M phase cell cycle arrest and modulated the levels of cyclin B and p-Cdc2 in Hec1A cells. Knockdown of p21 using specific siRNAs partially abrogated jaceosidin-induced cell growth inhibition. Additional mechanistic studies revealed that jaceosidin treatment resulted in an increase in phosphorylation of Cdc25C and ATM-Chk1/2. Ku55933, an ATM inhibitor, reversed jaceosidin-induced cell growth inhibition, in part. Moreover, jaceosidin treatment resulted in phosphorylation of ERK, and pretreatment with the ERK inhibitor, PD98059, attenuated cell growth inhibition by jaceosidin. These data suggest that jaceosidin, isolated from Japanese mugwort, modulates the ERK/ATM/Chk1/2 pathway, leading to inactivation of the Cdc2-cyclin B1 complex, followed by G2/M cell cycle arrest in endometrial cancer cells.
authors.affiliation: Department of Life & Nanopharmaceutical Science, Kyung Hee University, Seoul, South Korea.
authors.forename: Jong-Gyu
authors.initials: JG
authors.lastname: Lee
authors.forename: Ji-Hyun
authors.initials: JH
authors.lastname: Kim
authors.forename: Ji-Hye
authors.initials: JH
authors.lastname: Ahn
authors.forename: Kyung-Tae
authors.initials: KT
authors.lastname: Lee
authors.forename: Nam-In
authors.initials: NI
authors.lastname: Baek
authors.forename: Jung-Hye
authors.initials: JH
authors.lastname: Choi
mesh_terms: D019306:Artemisia / Q000737:chemistry*; D064007:Ataxia Telangiectasia Mutated Proteins; D016203:CDC2 Protein Kinase; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002455:Cell Division / Q000187:drug effects*; D045744:Cell Line, Tumor; D000071877:Checkpoint Kinase 1; D064447:Checkpoint Kinase 2; D019926:Cyclin B / Q000037:antagonists & inhibitors*; D018844:Cyclin-Dependent Kinases; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005260:Female; D005419:Flavonoids / Q000494:pharmacology*; D016195:G2 Phase / Q000187:drug effects*; D006801:Humans; D011494:Protein Kinases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D020687:cdc25 Phosphatases / Q000037:antagonists & inhibitors*
chemical_list: D018797:Cell Cycle Proteins; D019926:Cyclin B; D004268:DNA-Binding Proteins; D005419:Flavonoids; D025521:Tumor Suppressor Proteins; C477508:jaceosidin; D011494:Protein Kinases; D064447:Checkpoint Kinase 2; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C000605867:CHEK1 protein, human; C578634:CHEK2 protein, human; D000071877:Checkpoint Kinase 1; D017346:Protein Serine-Threonine Kinases; D016203:CDC2 Protein Kinase; C528899:CDK1 protein, human; D018844:Cyclin-Dependent Kinases; D020687:cdc25 Phosphatases