Nishioka, TakashiYamamoto, DaisukeZhu, TongGuo, JianjunKim, Sung-HoonChen, Chang-Yan2011-10-192011Nishioka, Takashi, Daisuke Yamamoto, Tongbo Zhu, Jinjin Guo, Sung-Hoon Kim, and Chang Yan Chen. 2011. Nicotine overrides DNA damage-induced G1/S restriction in lung cells. PLoS ONE 6(4): e18619.1932-6203http://nrs.harvard.edu/urn-3:HUL.InstRepos:5265952As 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 G1 arrest induced by y-radiation or BP in nicotine-treated murine or human lung epithelial cells. DNA synthesis was rapidly inhibited after exposure to y-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 y-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.en-USbiologybiochemistryproteinsnicotinic acetylcholine receptorsmolecular cell biologysignal transductiononogenic signalingmechanisms of signal transductionsignaling cascadesJournal Article2011-10-1910.1371/journal.pone.0018619