Activation of 5-lipoxygenase is required for nicotine mediated epithelial-mesenchymal transition and tumor cell growth

Cancer Lett. 2010 Jun 28;292(2):237-45. doi: 10.1016/j.canlet.2009.12.011. Epub 2010 Jan 12.


Nicotine is shown to be one of the carcinogenic agents for gastric cancer. Perturbation of epithelial-mesenchymal transition (EMT) results in loss of intracellular adhesions leading to tumor progression. In this study, we examined the underlying mechanism of the long-term effects of nicotine on tumor progression in human gastric cancer cells. Nicotine activated 5-lipoxygenase (5-LOX) in three gastric cancer cell lines (MKN-45, MKN-28 and AGS). Cells treated with nicotine dose- and time-dependently induced cell proliferation, invasion and suppressed apoptosis. In addition, cell cycle progression analysis revealed that activation of 5-LOX modulated the G1/S phase transition regulatory proteins and caused cell proliferation. MK886 (5-LOX activating protein inhibitor) mediated the induction of apoptosis by elevation of caspase-3 and Bax/Bcl2 ratio. Abrogation of 5-LOX repressed featured molecular markers of EMT (inactivation of E-cadherin and activation of transcriptional repressor Snail). Blockade of 5-LOX signaling resulted in downregulation of cyclin D1, matrix metalloproteinase (MMP-7, -9), urokinase plasminogen activator (uPA) and its receptor (uPAR), and pro-apoptotic proteins. Furthermore, suppression of Snail and induction of E-cadherin is extracellular signal-regulated kinase (Erk)-dependent. Thus, we conclude that the promotion effect of nicotine on cancer cell progression and EMT is mediated by Erk/5-LOX signaling pathway.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis
  • Arachidonate 5-Lipoxygenase / metabolism*
  • Base Sequence
  • Blotting, Western
  • Cell Cycle
  • Cell Line, Tumor
  • DNA Primers
  • Disease Progression
  • Enzyme Activation
  • Epithelial Cells / cytology*
  • Humans
  • Mesoderm / cytology*
  • Nicotine / pharmacology*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Stomach Neoplasms / enzymology
  • Stomach Neoplasms / pathology*


  • DNA Primers
  • Nicotine
  • Arachidonate 5-Lipoxygenase