Nicotine increases the resistance of lung cancer cells to cisplatin through enhancing Bcl-2 stability |
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| Authors: | T Nishioka L-Y Luo L Shen H He A Mariyannis W Dai C Chen |
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| Affiliation: | 1.Center for Drug Discovery, Northeastern University, 360 Huntington Avenue, Boston, MA 02115, USA;2.The First Affiliated Hospital of Nanchang University, Nanchang, China;3.Departments of Environmental Medicine and Biochemistry and Molecular Pharmacology, New York University, Tuxedo, NY, USA;4.Sahlgrenska Academy, Gothenburg University, Gothenburg, Sweden |
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| Abstract: | Background: Nicotine is able to activate mitogenic signalling pathways, which promote cell growth or survival as well as increase chemoresistance of cancer cells. However, the underlying mechanisms are not fully understood.Methods: In this study, we used immunoblotting and immunoprecipitation methods to test the ubiquitination and degradation of Bcl-2 affected by nicotine in lung cancer cells. Apoptotic assay was also used to measure the antagonising effect of nicotine on cisplatin-mediated cytotoxicity.Results: We demonstrated that the addition of nicotine greatly attenuated Bcl-2 ubiquitination and degradation, which further desensitised lung cancer cells to cisplatin-induced cytotoxicity. In this process, Bcl-2 was persistently phosphorylated in the cells cotreated with nicotine and cisplatin. Furthermore, Akt was proven to be responsible for sustained activation of Bcl-2 by nicotine, which further antagonised cisplatin-mediated apoptotic signalling.Conclusions: Our study suggested that nicotine activates its downstream signalling to interfere with the ubiquitination process and prevent Bcl-2 from being degraded in lung cancer cells, resulting in the increase of chemoresistance. |
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| Keywords: | nicotine cisplatin Bcl-2 Keap1 ubiquitination Akt chemoresistance |
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