Activation of 5-lipoxygenase is required for nicotine mediated epithelial-mesenchymal transition and tumor cell growth.
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.
Shin
Vivian Yvonne
VY
Department of Pharmacology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China. vyshin@hku.hk
Jin
Hong Chuan
HC
Ng
Enders Kai On
EK
Sung
Joseph Jao Yiu
JJ
Chu
Kent Man
KM
Cho
Chi Hin
CH
D017209:Apoptosis; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism*; D001483:Base Sequence; D015153:Blotting, Western; D002453:Cell Cycle; D045744:Cell Line, Tumor; D017931:DNA Primers; D018450:Disease Progression; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000166:cytology*; D006801:Humans; D008648:Mesoderm / Q000166:cytology*; D009538:Nicotine / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013274:Stomach Neoplasms / Q000201:enzymology / Q000473:pathology*
D017931:DNA Primers; D009538:Nicotine; D001094:Arachidonate 5-Lipoxygenase