title: Eupatilin, a dietary flavonoid, induces G2/M cell cycle arrest in human endometrial cancer cells.
abstract: This study is the first to investigate the antiproliferative effect of eupatilin in human endometrial cancer cells. Eupatilin, a naturally occurring flavonoid isolated from Artemisia princeps, has anti-inflammatory, anti-oxidative, and anti-tumor activities. In the present study, we investigated the potential effect of eupatilin on cell growth and its molecular mechanism of action in human endometrial cancer cells. Eupatilin was more potent than cisplatin in inhibiting cell viability in the human endometrial cancer cell lines Hec1A and KLE. Eupatilin showed relatively low cytotoxicity in normal human endometrial cells HES and HESC cells when compared to cisplatin. Eupatilin induced G2/M phase cell cycle arrest in a time- and dose-dependent manner, as indicated by flow cytometry analysis. In addition, treatment of Hec1A cells with eupatilin resulted in a significant increase in the expression of p21(WAF1/CIP1) and in the phosphorylation of Cdc25C and Cdc2. Knockdown of p21 using specific siRNAs significantly compromised eupatilin-induced cell growth inhibition. Interestingly, levels of mutant p53 in Hec1A cells decreased markedly upon treatment with eupatilin, and p53 siRNA significantly increased p21 expression. Moreover, eupatilin modulated the phosphorylation of protein kinases ERK1/2, Akt, ATM, and Chk2. These results suggest that eupatilin inhibits the growth of human endometrial cancer cells via G2/M phase cell cycle arrest through the up-regulation of p21 by the inhibition of mutant p53 and the activation of the ATM/Chk2/Cdc25C/Cdc2 checkpoint pathway.
authors.affiliation: College of Oriental Medicine, Kyung Hee University, Seoul, South Korea.
authors.forename: Jung-Hoon
authors.initials: JH
authors.lastname: Cho
authors.forename: Jong-Gyu
authors.initials: JG
authors.lastname: Lee
authors.forename: Yeong-In
authors.initials: YI
authors.lastname: Yang
authors.forename: Ji-Hyun
authors.initials: JH
authors.lastname: Kim
authors.forename: Ji-Hye
authors.initials: JH
authors.lastname: Ahn
authors.forename: Nam-In
authors.initials: NI
authors.lastname: Baek
authors.forename: Kyung-Tae
authors.initials: KT
authors.lastname: Lee
authors.forename: Jung-Hye
authors.initials: JH
authors.lastname: Choi
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D019306:Artemisia / Q000737:chemistry; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004717:Endometrium / Q000166:cytology*; D005260:Female; D005419:Flavonoids / Q000494:pharmacology*; D005434:Flow Cytometry; D016195:G2 Phase / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006801:Humans; D010766:Phosphorylation; D010936:Plant Extracts / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D005419:Flavonoids; D010936:Plant Extracts; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C045325:eupatilin; D017346:Protein Serine-Threonine Kinases; D002945:Cisplatin