title: Nicotine increases the resistance of lung cancer cells to cisplatin through enhancing Bcl-2 stability.
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.
authors.affiliation: Center for Drug Discovery, Northeastern University, 360 Huntington Avenue, Boston, MA 02115, USA.
authors.forename: T
authors.initials: T
authors.lastname: Nishioka
authors.affiliation: The First Affiliated Hospital of Nanchang University, Nanchang, China.
authors.forename: L-Y
authors.initials: LY
authors.lastname: Luo
authors.affiliation: Center for Drug Discovery, Northeastern University, 360 Huntington Avenue, Boston, MA 02115, USA.
authors.forename: L
authors.initials: L
authors.lastname: Shen
authors.affiliation: The First Affiliated Hospital of Nanchang University, Nanchang, China.
authors.forename: H
authors.initials: H
authors.lastname: He
authors.affiliation: Center for Drug Discovery, Northeastern University, 360 Huntington Avenue, Boston, MA 02115, USA.
authors.forename: A
authors.initials: A
authors.lastname: Mariyannis
authors.affiliation: Departments of Environmental Medicine and Biochemistry and Molecular Pharmacology, New York University, Tuxedo, NY, USA.
authors.forename: W
authors.initials: W
authors.lastname: Dai
authors.affiliation: 1] Center for Drug Discovery, Northeastern University, 360 Huntington Avenue, Boston, MA 02115, USA [2] Sahlgrenska Academy, Gothenburg University, Gothenburg, Sweden.
authors.forename: C
authors.initials: C
authors.lastname: Chen
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D002945:Cisplatin / Q000627:therapeutic use*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D051379:Mice; D009538:Nicotine / Q000494:pharmacology*; D011499:Protein Processing, Post-Translational / Q000187:drug effects*; D055550:Protein Stability / Q000187:drug effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D054875:Ubiquitination / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D019253:Proto-Oncogene Proteins c-bcl-2; D009538:Nicotine; D002945:Cisplatin