Nicotine Increases the Resistance of Lung Cancer Cells to Cisplatin Through Enhancing Bcl-2 Stability

Br J Cancer. 2014 Apr 2;110(7):1785-92. doi: 10.1038/bjc.2014.78. Epub 2014 Feb 18.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / therapeutic use*
  • Apoptosis / drug effects
  • Cisplatin / therapeutic use*
  • Drug Resistance, Neoplasm / drug effects*
  • Humans
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / metabolism
  • Mice
  • Nicotine / pharmacology*
  • Protein Processing, Post-Translational / drug effects*
  • Protein Stability / drug effects
  • Proto-Oncogene Proteins c-bcl-2 / metabolism*
  • Tumor Cells, Cultured
  • Ubiquitination / drug effects
  • Up-Regulation / drug effects

Substances

  • Antineoplastic Agents
  • Proto-Oncogene Proteins c-bcl-2
  • Nicotine
  • Cisplatin