title: Activation of Akt/GSK3β and Akt/Bcl-2 signaling pathways in nickel-transformed BEAS-2B cells.
abstract: The Akt signaling pathway has been implicated in a wide range of cellular functions involving cell survival and proliferation, angiogenesis, metabolism and cell migration. Accumulating evidence suggests that Akt perturbations play an important role in human malignancy. Here, we investigated Akt perturbation in nickel-transformed cells. Chronic treatment of human bronchial epithelial BEAS-2B cells with low doses of nickel chloride resulted in cell transformation demonstrated by anchorage-independent (AI) growth, increased cell growth and alterations of cell growth pattern. Western blot assays show that phosphorylation of Akt at Ser473, but not that of p38, JNK and ERK, was increased in nickel-transformed cells compared with controls. Inhibition of Akt or PI3K by pharmacological or biochemical interference suppressed nickel AI growth and cell growth of transformed cells. Activation of Akt led to inhibition of GSK3β by phosphorylation at Ser9 in nickel-transformed cells. In addition, two major anti-apoptotic proteins of the Bcl family, Bcl-2 and Bcl-XL, were increased in nickel-transformed cells. By employing the small interfering RNA technique (siRNA), our results showed that siRNA Akt attenuated the expression of Bcl-2 and Bcl-XL in nickel-transformed cells, indicating that induction of Bcl-2 and Bcl-XL was likely mediated through Akt. ROS generation was decreased in nickel-transformed cells compared with controls. Moreover, down-regulation of retinoblastoma protein (Rb) was observed in nickel-transformed cells. Taken together, these findings demonstrate that activation of Akt, followed by GSK3β inhibition and Bcl-2, Bcl-XL up-regulation and decrease of ROS generation, along with a synergistic effect of Rb down-regulation may cause apoptosis resistance, contributing to the overall mechanism of nickel carcinogenesis.
authors.affiliation: Institute of Chronic Non-Communicable Disease, Hubei Provincial Center for Disease Control and Prevention, Wuhan 430079, P.R. China.
authors.forename: Jing-Ju
authors.initials: JJ
authors.lastname: Pan
authors.forename: Qing-Shan
authors.initials: QS
authors.lastname: Chang
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.forename: Young-Ok
authors.initials: YO
authors.lastname: Son
authors.forename: Jiankang
authors.initials: J
authors.lastname: Liu
authors.forename: Zhuo
authors.initials: Z
authors.lastname: Zhang
authors.forename: Yong-Yi
authors.initials: YY
authors.lastname: Bi
authors.forename: Xianglin
authors.initials: X
authors.lastname: Shi
mesh_terms: D002273:Carcinogens / Q000494:pharmacology*; D002461:Cell Line, Transformed; D002471:Cell Transformation, Neoplastic / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009532:Nickel / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D002273:Carcinogens; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; D016160:Retinoblastoma Protein; D016159:Tumor Suppressor Protein p53; C022838:nickel chloride; D009532:Nickel; D019869:Phosphatidylinositol 3-Kinases; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases; D038362:Glycogen Synthase Kinase 3