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 G1 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.
Highlights
Tobacco smoke imposes a high risk for human malignancies, especially for lung cancer, because it contains more than 4000 components, most of which are well defined carcinogens [1,2]
Since most of tobacco smoke components are genotoxic, we first tested the influence of nicotine on genotoxic stress in murine LA4 or human BEAS-2B lung epithelial cells. [3H]-thymidine incorporation assay was performed (Fig. 1a)
We have investigated the mechanism by which nicotine perturbs c-irradiation- or BP treatment-induced G1/S checkpoints
Summary
Tobacco smoke imposes a high risk for human malignancies, especially for lung cancer, because it contains more than 4000 components, most of which are well defined carcinogens [1,2]. Cells do not progress into S or M phase before lesions are properly repaired by activating DNA damage checkpoint [15,16]. The reduction of the sensitivity to genotoxic agents closely links to loss of the checkpoint function that permits cells a high rate of genomic adaptation to acquire a growth advantage. DNA damage checkpoint acts as a process of signal transduction to transmit information from damaged lesions to cell cycle regulators. In this process, ATM for double strand DNA breaks and ATR for single strand damages appear to be activated and further mediates a cascade of protein phosphorylation of effector checkpoint kinases (including Chk and Chk2) [17,18,19,20]. Many components in tobacco smoke have been proved to be genotoxic, the combination effect of nicotine and tobacco-related genotoxic reagents or therapeutic radiation on DNA damage response remains unexplored
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