title: Nicotine overrides DNA damage-induced G1/S restriction in lung cells.
abstract: As an addictive substance, nicotine has been suggested to facilitate pro-survival activities (such as anchorage-independent growth or angiogenesis) and the establishment of drug resistance to anticancer therapy. Tobacco smoking consists of a variety of carcinogens [such as benzopyrene (BP) and nitrosamine derivatives] that are able to cause DNA double strand breaks. However, the effect of nicotine on DNA damage-induced checkpoint response induced by genotoxins remains unknown. In this study, we investigated the events occurred during G(1) arrest induced by γ-radiation or BP in nicotine-treated murine or human lung epithelial cells. DNA synthesis was rapidly inhibited after exposure to γ-radiation or BP treatment, accompanied with the activation of DNA damage checkpoint. When these cells were co-treated with nicotine, the growth restriction was compromised, manifested by upregulation of cyclin D and A, and attenuation of Chk2 phosphorylation. Knockdown of cyclin D or Chk2 by the siRNAs blocked nicotine-mediated effect on DNA damage checkpoint activation. However, nicotine treatment appeared to play no role in nocodazole-induced mitotic checkpoint activation. Overall, our study presented a novel observation, in which nicotine is able to override DNA damage checkpoint activated by tobacco-related carcinogen BP or γ-irradiation. The results not only indicates the potentially important role of nicotine in facilitating the establishment of genetic instability to promote lung tumorigenesis, but also warrants a dismal prognosis for cancer patients who are smokers, heavily exposed second-hand smokers or nicotine users.
authors.affiliation: Department of Radiation Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Takashi
authors.initials: T
authors.lastname: Nishioka
authors.forename: Daisuke
authors.initials: D
authors.lastname: Yamamoto
authors.forename: Tongbo
authors.initials: T
authors.lastname: Zhu
authors.forename: Jinjin
authors.initials: J
authors.lastname: Guo
authors.forename: Sung-Hoon
authors.initials: SH
authors.lastname: Kim
authors.forename: Chang Yan
authors.initials: CY
authors.lastname: Chen
mesh_terms: D000818:Animals; D001580:Benzopyrenes / Q000494:pharmacology; D002273:Carcinogens; D019925:Cyclin A / Q000096:biosynthesis; D019938:Cyclin D1 / Q000096:biosynthesis; D004249:DNA Damage / Q000187:drug effects*; D004847:Epithelial Cells / Q000166:cytology; D016193:G1 Phase; D005720:Gamma Rays; D005731:Ganglionic Stimulants / Q000494:pharmacology; D006801:Humans; D008168:Lung / Q000187:drug effects*; D051379:Mice; D009154:Mutation; D009538:Nicotine / Q000494:pharmacology*; D015739:Nocodazole / Q000494:pharmacology; D010766:Phosphorylation; D016196:S Phase
chemical_list: D001580:Benzopyrenes; D002273:Carcinogens; D019925:Cyclin A; D005731:Ganglionic Stimulants; D019938:Cyclin D1; D009538:Nicotine; D015739:Nocodazole