Induction of osteopontin expression by nicotine and cigarette smoke in the pancreas and pancreatic ductal adenocarcinoma cells

Galina Chipitsyna, Qiaoke Gong, Rathai Anandanadesan, Amer Alnajar, Surinder Kumar Batra, Uwe A. Wittel, Diane M. Cullen, Mohammed P. Akhter, David T. Denhardt, Charles J. Yeo, Hwyda A. Arafat

Research output: Contribution to journalArticle

27 Citations (Scopus)

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 languageEnglish (US)
Pages (from-to)276-285
Number of pages10
JournalInternational Journal of Cancer
Volume125
Issue number2
DOIs
StatePublished - Jul 15 2009

Fingerprint

Osteopontin
Nicotine
Smoke
Tobacco Products
Pancreas
Adenocarcinoma
Messenger RNA
JNK Mitogen-Activated Protein Kinases
Genistein
Pancreatic Ducts
Phosphoproteins
Nicotinic Receptors
Cholinergic Antagonists
Mitogen-Activated Protein Kinases
Protein-Tyrosine Kinases
Transcriptional Activation
Signal Transduction
Neoplasms
Cell Survival
Up-Regulation

Keywords

  • Cigarette smoke
  • Nicotine
  • Osteopontin
  • Pancreatic cancer

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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 Kumar; 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 journalArticle

Chipitsyna, G, Gong, Q, Anandanadesan, R, Alnajar, A, Batra, SK, Wittel, UA, Cullen, DM, Akhter, MP, Denhardt, DT, Yeo, CJ & Arafat, HA 2009, 'Induction of osteopontin expression by nicotine and cigarette smoke in the pancreas and pancreatic ductal adenocarcinoma cells', International Journal of Cancer, vol. 125, no. 2, pp. 276-285. https://doi.org/10.1002/ijc.24388
Chipitsyna, Galina ; Gong, Qiaoke ; Anandanadesan, Rathai ; Alnajar, Amer ; Batra, Surinder Kumar ; Wittel, Uwe A. ; Cullen, Diane M. ; Akhter, Mohammed P. ; Denhardt, David T. ; Yeo, Charles J. ; Arafat, Hwyda A. / Induction of osteopontin expression by nicotine and cigarette smoke in the pancreas and pancreatic ductal adenocarcinoma cells. In: International Journal of Cancer. 2009 ; Vol. 125, No. 2. pp. 276-285.
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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.",
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AU - Batra, Surinder Kumar

AU - Wittel, Uwe A.

AU - Cullen, Diane M.

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AU - Yeo, Charles J.

AU - Arafat, Hwyda A.

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