title: Jaridonin-induced G2/M phase arrest in human esophageal cancer cells is caused by reactive oxygen species-dependent Cdc2-tyr15 phosphorylation via ATM-Chk1/2-Cdc25C pathway.
abstract: Jaridonin, a novel diterpenoid from Isodon rubescens, has been shown previously to inhibit proliferation of esophageal squamous cancer cells (ESCC) through G2/M phase cell cycle arrest. However, the involved mechanism is not fully understood. In this study, we found that the cell cycle arrest by Jaridonin was associated with the increased expression of phosphorylation of ATM at Ser1981 and Cdc2 at Tyr15. Jaridonin also resulted in enhanced phosphorylation of Cdc25C via the activation of checkpoint kinases Chk1 and Chk2, as well as in increased phospho-H2A.X (Ser139), which is known to be phosphorylated by ATM in response to DNA damage. Furthermore, Jaridonin-mediated alterations in cell cycle arrest were significantly attenuated in the presence of NAC, implicating the involvement of ROS in Jaridonin's effects. On the other hand, addition of ATM inhibitors reversed Jaridonin-related activation of ATM and Chk1/2 as well as phosphorylation of Cdc25C, Cdc2 and H2A.X and G2/M phase arrest. In conclusion, these findings identified that Jaridonin-induced cell cycle arrest in human esophageal cancer cells is associated with ROS-mediated activation of ATM-Chk1/2-Cdc25C pathway.
authors.affiliation: Clinical Pharmacology Laboratory, Henan Province People's Hospital, No. 7, Wei Wu Road, Zhengzhou, Henan, China.
authors.forename: Yong-Cheng
authors.initials: YC
authors.lastname: Ma
authors.affiliation: Department of Quality Detection and Management, Henan University of Animal Husbandry and Economy, Zhengzhou, Henan, China.
authors.forename: Nan
authors.initials: N
authors.lastname: Su
authors.affiliation: School of Pharmaceutical Sciences, Zhengzhou University, No. 100, Science Avenue, Zhengzhou, Henan, China.
authors.forename: Xiao-Jing
authors.initials: XJ
authors.lastname: Shi
authors.affiliation: School of Pharmaceutical Sciences, Zhengzhou University, No. 100, Science Avenue, Zhengzhou, Henan, China.
authors.forename: Wen
authors.initials: W
authors.lastname: Zhao
authors.affiliation: School of Pharmaceutical Sciences, Zhengzhou University, No. 100, Science Avenue, Zhengzhou, Henan, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Ke
authors.affiliation: Department of Urology, University of California, Irvine, Orange, CA, USA; Department of Pharmacology, University of California, Irvine, Orange, CA, USA; Department of Pharmaceutical Sciences, University of California, Irvine, Orange, CA, USA.
authors.forename: Xiaolin
authors.initials: X
authors.lastname: Zi
authors.affiliation: Clinical Pharmacology Laboratory, Henan Province People's Hospital, No. 7, Wei Wu Road, Zhengzhou, Henan, China.
authors.forename: Ning-Min
authors.initials: NM
authors.lastname: Zhao
authors.affiliation: Clinical Pharmacology Laboratory, Henan Province People's Hospital, No. 7, Wei Wu Road, Zhengzhou, Henan, China.
authors.forename: Yu-Hua
authors.initials: YH
authors.lastname: Qin
authors.affiliation: Clinical Pharmacology Laboratory, Henan Province People's Hospital, No. 7, Wei Wu Road, Zhengzhou, Henan, China.
authors.forename: Hong-Wei
authors.initials: HW
authors.lastname: Zhao
authors.affiliation: School of Pharmaceutical Sciences, Zhengzhou University, No. 100, Science Avenue, Zhengzhou, Henan, China. Electronic address: liuhm@zzu.edu.cn.
authors.forename: Hong-Min
authors.initials: HM
authors.lastname: Liu
mesh_terms: D000970:Antineoplastic Agents / Q000633:toxicity*; D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism*; D016203:CDC2 Protein Kinase / Q000378:metabolism*; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects*; D045744:Cell Line, Tumor; D000071877:Checkpoint Kinase 1; D064447:Checkpoint Kinase 2 / Q000378:metabolism*; D045786:Diterpenes, Kaurane / Q000633:toxicity*; D004938:Esophageal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D016195:G2 Phase / Q000187:drug effects*; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D045786:Diterpenes, Kaurane; D017382:Reactive Oxygen Species; C587044:jaridonin; D011494:Protein Kinases; D064447:Checkpoint Kinase 2; D064007:Ataxia Telangiectasia Mutated Proteins; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; D016203:CDC2 Protein Kinase; D005978:Glutathione
keywords: ATM; Cell cycle arrest; Ent-kaurene diterpenoid; ROS; Rabdosia rubescens