title: Anti-apoptotic proteins and catalase-dependent apoptosis resistance in nickel chloride-transformed human lung epithelial cells.
abstract: Chronic exposure to nickel compounds is associated with increased incidence of certain types of human cancer, including lung and nasal cancers. Despite intensive investigation, the oncogenic processes remain poorly understood. Apoptosis resistance is a key feature for tumor cells to escape physiological surveillance and acquire growth advantage over normal cells. Although NiCl2 exposure induces transformation of human lung epithelial cells, little information is available with regard to its molecular mechanisms, it is also not clear if the transformed cells are apoptosis resistant and tumorigenic. We explored the apoptosis resistance properties of nickel chloride‑transformed human lung epithelial cells and the underlying mechanisms. The results showed that transformed BEAS-2B human lung epithelial cells are resistant to NiCl2-induced apoptosis. They have increased Bcl-2, Bcl-xL and catalase protein levels over the passage matched non‑transformed counterparts. The mechanisms of apoptosis resistance are mitochondria‑mediated and caspase-dependent. Forced overexpression of Bcl-2, Bcl-xL and catalase proteins reduced NiCl2-induced cell death; siRNA‑mediated knockdown of their expression sensitized the cells to nickel-induced apoptosis, suggesting that Bcl-2, Bcl-xl and catalase protein expression plays a critical role in apoptosis resistance. Akt also participates in this process, as its overexpression increases Bcl-xL protein expression levels and attenuates NiCl2-induced apoptosis. Furthermore, transformed cells are tumorigenic in a xenograft model. Together, these results demonstrate that nickel-transformed cells are apoptosis‑resistant and tumorigenic. Increased expression of Bcl-2, Bcl-xL and catalase proteins are important mechanisms contributing to transformed cell oncogenic properties.
authors.affiliation: Department of Internal Medicine, Henan Provincial People's Hospital, Zhengzhou University, Zhengzhou, Henan 450000, P.R. China.
authors.forename: Yu-Xiu
authors.initials: YX
authors.lastname: Yang
authors.forename: Xiu-Ling
authors.initials: XL
authors.lastname: Li
authors.forename: Lei
authors.initials: L
authors.lastname: Wang
authors.forename: Shuang-Yin
authors.initials: SY
authors.lastname: Han
authors.forename: Yan-Rui
authors.initials: YR
authors.lastname: Zhang
authors.forename: Poyil
authors.initials: P
authors.lastname: Pratheeshkumar
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.forename: Jian
authors.initials: J
authors.lastname: Lu
authors.forename: Yuan-Qin
authors.initials: YQ
authors.lastname: Yin
authors.forename: Li-Juan
authors.initials: LJ
authors.lastname: Sun
authors.forename: Amit
authors.initials: A
authors.lastname: Budhraja
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Hitron
authors.forename: Song-Ze
authors.initials: SZ
authors.lastname: Ding
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D002374:Catalase / Q000096:biosynthesis / Q000235:genetics*; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced / Q000235:genetics*; D004847:Epithelial Cells / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D009532:Nickel / Q000633:toxicity; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000235:genetics*; D034741:RNA, Small Interfering; D051020:bcl-X Protein / Q000096:biosynthesis / Q000235:genetics*
chemical_list: C494811:BCL2L1 protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; D051020:bcl-X Protein; C022838:nickel chloride; D009532:Nickel; D002374:Catalase