Abstract
Pancreatic ductal adenocarcinoma (PDA) is a lethal disease with etiological association with cigarette smoking. Nicotine, an important component of cigarettes, exists at high concentrations in the bloodstream of smokers. Osteopontin (OPN) is a secreted phosphoprotein that confers on cancer cells a migratory phenotype and activates signaling pathways that induce cell survival, proliferation, invasion, and metastasis. Here, we investigated the potential molecular basis of nicotine's role in PDA through studying its effect on OPN. Nicotine significantly (p <0.02) increased OPN mRNA and protein secretion in PDA cells through activation of the OPN gene promoter. The OPN mRNA induction was inhibited by the nicotinic acetylcholine receptor antagonist, mechamylamine. Further, the tyrosine kinase inhibitor genistein inhibited the nicotine-mediated induction of OPN, suggesting that mitogen activated protein kinase signaling mechanism is involved. Nicotine activated the phosphorylation of ERK1/2, but not p38 or c-Jun NH2-terminal MAP kinases. Inhibition of ERK1/2 activation reduced the nicotine-induced OPN synthesis. Rats exposed to cigarette smoke showed a dose-dependent increase in pancreatic OPN that paralleled the rise of pancreatic and plasma nicotine levels. Analysis of cancer tissue from invasive PDA patients, the majority of whom were smokers, showed the presence of significant amounts of OPN in the malignant ducts and the surrounding pancreatic acini. Our data suggest that nicotine may contribute to PDA pathogenesis through upregulation of OPN. They provide the first insight into a nicotine-initiated signal transduction pathway that regulates OPN as a possible tumorigenic mechanism in PDA.
| Original language | English |
|---|---|
| Pages (from-to) | 276-285 |
| Number of pages | 10 |
| Journal | International Journal of Cancer |
| Volume | 125 |
| Issue number | 2 |
| DOIs | |
| State | Published - Jul 15 2009 |
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All Science Journal Classification (ASJC) codes
- Cancer Research
- Oncology
- Medicine(all)
Cite this
Induction of osteopontin expression by nicotine and cigarette smoke in the pancreas and pancreatic ductal adenocarcinoma cells. / Chipitsyna, Galina; Gong, Qiaoke; Anandanadesan, Rathai; Alnajar, Amer; Batra, Surinder K.; Wittel, Uwe A.; Cullen, Diane M.; Akhter, Mohammed P.; Denhardt, David T.; Yeo, Charles J.; Arafat, Hwyda A.
In: International Journal of Cancer, Vol. 125, No. 2, 15.07.2009, p. 276-285.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Induction of osteopontin expression by nicotine and cigarette smoke in the pancreas and pancreatic ductal adenocarcinoma cells
AU - Chipitsyna, Galina
AU - Gong, Qiaoke
AU - Anandanadesan, Rathai
AU - Alnajar, Amer
AU - Batra, Surinder K.
AU - Wittel, Uwe A.
AU - Cullen, Diane M.
AU - Akhter, Mohammed P.
AU - Denhardt, David T.
AU - Yeo, Charles J.
AU - Arafat, Hwyda A.
PY - 2009/7/15
Y1 - 2009/7/15
N2 - Pancreatic ductal adenocarcinoma (PDA) is a lethal disease with etiological association with cigarette smoking. Nicotine, an important component of cigarettes, exists at high concentrations in the bloodstream of smokers. Osteopontin (OPN) is a secreted phosphoprotein that confers on cancer cells a migratory phenotype and activates signaling pathways that induce cell survival, proliferation, invasion, and metastasis. Here, we investigated the potential molecular basis of nicotine's role in PDA through studying its effect on OPN. Nicotine significantly (p <0.02) increased OPN mRNA and protein secretion in PDA cells through activation of the OPN gene promoter. The OPN mRNA induction was inhibited by the nicotinic acetylcholine receptor antagonist, mechamylamine. Further, the tyrosine kinase inhibitor genistein inhibited the nicotine-mediated induction of OPN, suggesting that mitogen activated protein kinase signaling mechanism is involved. Nicotine activated the phosphorylation of ERK1/2, but not p38 or c-Jun NH2-terminal MAP kinases. Inhibition of ERK1/2 activation reduced the nicotine-induced OPN synthesis. Rats exposed to cigarette smoke showed a dose-dependent increase in pancreatic OPN that paralleled the rise of pancreatic and plasma nicotine levels. Analysis of cancer tissue from invasive PDA patients, the majority of whom were smokers, showed the presence of significant amounts of OPN in the malignant ducts and the surrounding pancreatic acini. Our data suggest that nicotine may contribute to PDA pathogenesis through upregulation of OPN. They provide the first insight into a nicotine-initiated signal transduction pathway that regulates OPN as a possible tumorigenic mechanism in PDA.
AB - Pancreatic ductal adenocarcinoma (PDA) is a lethal disease with etiological association with cigarette smoking. Nicotine, an important component of cigarettes, exists at high concentrations in the bloodstream of smokers. Osteopontin (OPN) is a secreted phosphoprotein that confers on cancer cells a migratory phenotype and activates signaling pathways that induce cell survival, proliferation, invasion, and metastasis. Here, we investigated the potential molecular basis of nicotine's role in PDA through studying its effect on OPN. Nicotine significantly (p <0.02) increased OPN mRNA and protein secretion in PDA cells through activation of the OPN gene promoter. The OPN mRNA induction was inhibited by the nicotinic acetylcholine receptor antagonist, mechamylamine. Further, the tyrosine kinase inhibitor genistein inhibited the nicotine-mediated induction of OPN, suggesting that mitogen activated protein kinase signaling mechanism is involved. Nicotine activated the phosphorylation of ERK1/2, but not p38 or c-Jun NH2-terminal MAP kinases. Inhibition of ERK1/2 activation reduced the nicotine-induced OPN synthesis. Rats exposed to cigarette smoke showed a dose-dependent increase in pancreatic OPN that paralleled the rise of pancreatic and plasma nicotine levels. Analysis of cancer tissue from invasive PDA patients, the majority of whom were smokers, showed the presence of significant amounts of OPN in the malignant ducts and the surrounding pancreatic acini. Our data suggest that nicotine may contribute to PDA pathogenesis through upregulation of OPN. They provide the first insight into a nicotine-initiated signal transduction pathway that regulates OPN as a possible tumorigenic mechanism in PDA.
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U2 - 10.1002/ijc.24388
DO - 10.1002/ijc.24388
M3 - Article
VL - 125
SP - 276
EP - 285
JO - International Journal of Cancer
JF - International Journal of Cancer
SN - 0020-7136
IS - 2
ER -