title: ERK/GSK3β signaling is involved in atractylenolide I-induced apoptosis and cell cycle arrest in melanoma cells.
abstract: Novel agents need to be developed to overcome the limitations of the current melanoma therapeutics. Atractylenolide I (AT-I) is a sesquiterpene compound isolated from atractylodis macrocephalae rhizoma. Previous findings demonstrated that AT-I exhibited cytotoxic action in melanoma cells. However, the molecular mechanisms of AT‑1's anti-melanoma properties remain to be elucidated. In the present study, the cell cycle-arrest and apoptosis-promoting effects as well as the ERK/GSK3β signaling-related mechanism of action of AT-I were examined. B16 melanoma cells were treated with various concentrations of AT-1 (50, 75 and 100 µM) for 48 or 72 h. Cell cycle and apoptosis were analyzed by flow cytometry. Protein expression levels were detected by western blot analysis. AT-I treatment induced G1 phase arrest, which was accompanied by increased p21 and decreased CDK2 protein expression levels. Apoptosis was observed after AT-I treatment for 72 h, which was accompanied by activated caspase‑3 and ‑8. AT-I treatment significantly decreased phospho-ERK, phospho-GSK3β, c-Jun and increased p53 protein expression levels. Lithium chloride (LiCl, 5 mM), a GSK3β inhibitor, treatment alone did not increase the apoptosis of B16 cells, while pretreatment with LiCl markedly reversed AT-I-induced apoptosis. Additionally, AT-I-induced G1 phase arrest was partially reversed by LiCl pretreatment. In conclusion, ERK/GSK3β signaling was involved in the apoptotic and G1 phase arrest effects of AT-I in melanoma cells.
authors.affiliation: Center for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong, P.R. China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Ye
authors.affiliation: Center for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong, P.R. China.
authors.forename: Xiao-Juan
authors.initials: XJ
authors.lastname: Chao
authors.affiliation: Center for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong, P.R. China.
authors.forename: Jin-Feng
authors.initials: JF
authors.lastname: Wu
authors.affiliation: Center for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong, P.R. China.
authors.forename: Brian Chi-Yan
authors.initials: BC
authors.lastname: Cheng
authors.affiliation: Center for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong, P.R. China.
authors.forename: Tao
authors.initials: T
authors.lastname: Su
authors.affiliation: Center for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong, P.R. China.
authors.forename: Xiu-Qiong
authors.initials: XQ
authors.lastname: Fu
authors.affiliation: Center for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong, P.R. China.
authors.forename: Ting
authors.initials: T
authors.lastname: Li
authors.affiliation: Center for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong, P.R. China.
authors.forename: Hui
authors.initials: H
authors.lastname: Guo
authors.affiliation: Center for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong, P.R. China.
authors.forename: Anfernee Kai-Wing
authors.initials: AK
authors.lastname: Tse
authors.affiliation: Center for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong, P.R. China.
authors.forename: Hiu-Yee
authors.initials: HY
authors.lastname: Kwan
authors.affiliation: Center for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong, P.R. China.
authors.forename: Juan
authors.initials: J
authors.lastname: Du
authors.affiliation: Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, P.R. China.
authors.forename: Gui-Xin
authors.initials: GX
authors.lastname: Chou
authors.affiliation: Center for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong, P.R. China.
authors.forename: Zhi-Ling
authors.initials: ZL
authors.lastname: Yu
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D038362:Glycogen Synthase Kinase 3 / Q000096:biosynthesis* / Q000235:genetics; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D007783:Lactones / Q000008:administration & dosage*; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D051379:Mice; D048052:Mitogen-Activated Protein Kinase 3 / Q000096:biosynthesis* / Q000235:genetics; D009363:Neoplasm Proteins / Q000096:biosynthesis; D012717:Sesquiterpenes / Q000008:administration & dosage*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D007783:Lactones; D009363:Neoplasm Proteins; D012717:Sesquiterpenes; C424804:atractylenolide I; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D048052:Mitogen-Activated Protein Kinase 3; D038362:Glycogen Synthase Kinase 3