The tobacco-specific carcinogen, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone stimulates proliferation of immortalized human pancreatic duct epithelia through β-adrenergic transactivation of EGF receptors

Askari, Minoo; Tsao, Ming‐Sound; Schüller, Hildegard M.

doi:10.1007/s00432-005-0002-7

Cited by 91 publications

(117 citation statements)

References 30 publications

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“…β-AR agonists and EGF increase EGFR phosphorylation EGFR transactivation was caused by binding of β-AR agonist to its receptor [5] . Both cells were treated with β-AR ligands alone or in combinations for 10 min.…”

Section: β-Ar Agonists and Forskolin Increase Camp Accumulationmentioning

confidence: 99%

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HIF-1α links β-adrenoceptor agonists and pancreatic cancer cells under normoxic condition

Qing

Zhang

et al. 2009

Acta Pharmacol Sin

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Aim: To examine whether β-adrenoceptor (β-AR) agonists can induce hypoxia-inducible factor (HIF)-1α accumulation which then upregulate the expression of its target genes in pancreatic cancer cells at normoxia, and to further elucidate the mechanism involved. Methods: Pulse-chase assay, RT-PCR, and Western blot were employed to detect the effects of β-AR agonists and antagonists, siRNA as well as several inhibitors of signal transduction pathways on MIA PaCa2 and BxPC-3 pancreatic cancer cells. Results: Treatment of pancreatic cancer cell lines with β-AR agonists led to accumulation of HIF-1α and then up-regulated expression of its target genes independently of oxygen levels. The induction was partly or completely inhibited not only by β-AR antagonists but also by inhibitors of PKA transduction pathways and by siHIF-1α. Both β1-AR and β2-AR agonists produced the above-mentioned effects, but β2-AR agonist was more potent. Conclusion: Activation of β-AR receptor transactivates epidermal growth factor receptor (EGFR) and then elicites Akt and ERK1/2 in a PKA-dependent manner, which together up-regulate levels of HIF-1α and downstream target genes independently of oxygen level. Our data suggest a novel mechanism in pancreatic cancer cells that links β-AR and HIF-1α signaling under normoxic conditions, with implications for the control of glucose transport, angiogenesis and metastasis.

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Section: β-Ar Agonists and Forskolin Increase Camp Accumulationmentioning

confidence: 99%

“…A normal pancreatic duct epithelial cell line and several pancreatic cancer cell lines express β1 and/or β2-ARs as well as epidermal growth factor receptor (EGFR) including Panc-1, BXPC-3, PC-2, PC-3, and HPDE6-c7. Moreover, the EGFR is frequently over-expressed in pancreatic cancer [4][5][6] .…”

Section: Introductionmentioning

confidence: 99%

HIF-1α links β-adrenoceptor agonists and pancreatic cancer cells under normoxic condition

Qing

Zhang

et al. 2009

Acta Pharmacol Sin

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“…However, in these cells, carcinogenic events are unlikely to be mediated by a disturbance of the physiologic regulation. In vitro, the impact of polycyclic aromatic hydrocarbons and NNK, two cigarette smoke-associated carcinogens, was investigated in immortalized pancreatic ductal cells [61][62]. In these studies, NNK increased the proliferation of pancreatic ductal cells by beta-adrenergic receptor transactivation of EGFR with downstream ERK 1/2 phosphorylation, indicating one potential pro-carcinogenic effect of NNK [61].…”

Section: Inflammation Alters Regulation Of Ductal Genesmentioning

confidence: 99%

Cigarette smoke-induced pancreatic damage—experimental data

Wittel

Hopt

Batra

2008

Langenbecks Arch Surg

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“…35 A recent study reported NNK, the tobacco-specific carcinogen, stimulates proliferation of HPDE6-c7 cells. 36 To determine a potential mechanistic effect of cigarette smoke on biologically relevant cell type, we determined specific structure-activity effects of methylanthracene isomers, which are some of the most prevalent polycyclic aromatic hydrocarbons found in cigarette smoke condensates, 37 on GJIC and stem cell markers in the pluripotent pancreatic stem cell line (HPDE6-E6E7c7).…”

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confidence: 99%

Cigarette smoke components inhibited intercellular communication and differentiation in human pancreatic ductal epithelial cells

Tai

Upham

Olson

et al. 2007

Intl Journal of Cancer

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Smoking is a well-documented risk factor for the development of pancreatic adenocarcinoma. Although the most abundant polycyclic aromatic hydrocarbons (PAHs) in cigarette smoke are methylated anthracenes and phenanthrenes, the epigenetic toxicity of these compounds has not been extensively studied. We previously showed that methylanthracenes, which possess a bay-like structure, affect epigenetic events such as an induced release of arachidonic acid, inhibition of gap junctional intercellular communication (GJIC) and induction of mitogen-activated protein kinases in a pluripotent rat liver epithelial stem cell line. Anthracenes with no bay-like structures were inactive. These biological effects are all molecular events associated with the promotional phase of cancer. A human immortalized, nontumorigenic pancreatic ductal epithelial cell line, H6c7, was examined to study the epigenetic toxicity of PAHs related to pancreatic cancer by using scrape-loading dye transfer, immunostaining, RT-PCR and telomerase assay methods. H6c7 cells were GJIC-incompetent and exhibited high telomerase activity when grown in growth factor and hormonesupplemented medium. In the presence of the cAMP elevating drugs (forskolin and IBMX) the cells became GJIC competent and expressed connexins. Telomerase activity was also decreased by cAMP elevating drug treatment. After induction of cAMP, 1-methylanthracene with bay-like structures inhibited GJIC, whereas the 2-methylanthracene lacking a bay-like structure had no effect on GJIC. Telomerase activity remained high in 1-methylanthracene treatment but not with 2-methylanthracene. These results indicate that a prominent component of cigarette smoke, namely methylanthracenes with distinct structural configurations, could be a potential etiological agent contributing to the epigenetic events of pancreatic cancer. ' 2007 Wiley-Liss, Inc.Key words: connexin 36; telomerase; PAH; gap junction Pancreatic cancer is the fourth most common cause of cancerrelated death in the United States. 1,2 Incidence in the developed world parallels the United States, and in undeveloped nations the incidence is lower, which could be due to underreporting. 3 There are no early screening tests and no universally-effective treatment options, making this disease one of the most fatal cancers known, with a 5-year survival rate of less than 5%. 1,3-5 A recent article even suggested no patients are actually ''cured'' of this disease. 6 Although several risk factors, such as diet, have been associated with pancreatic cancer, cigarette smoking is the only unequivocal risk factor that has been identified. 1,7-9 The incidence of pancreatic cancer is 50-90% higher among blacks in the United States than whites. This disparity has been linked primarily to cigarette smoking-and to a lesser extent diabetes-in men, 10 again indicating the significance of tobacco smoke in the incidence of pancreatic cancer.Although cigarette smoke has been identified as one etiological cause of pancreatic cancer, the underlying molecular mechanism ca...

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The tobacco-specific carcinogen, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone stimulates proliferation of immortalized human pancreatic duct epithelia through β-adrenergic transactivation of EGF receptors

Abstract: These findings suggest that the NNK -mediated beta-adrenergic receptor transactivation of the EGFR and phosphorylation of Erk1/2 in immortalized human pancreatic duct epithelial cells as a novel mechanism might contribute to the development of tobacco-associated pancreatic carcinogenesis.

Cited by 91 publications

References 30 publications

HIF-1α links β-adrenoceptor agonists and pancreatic cancer cells under normoxic condition

HIF-1α links β-adrenoceptor agonists and pancreatic cancer cells under normoxic condition

Cigarette smoke-induced pancreatic damage—experimental data

Cigarette smoke components inhibited intercellular communication and differentiation in human pancreatic ductal epithelial cells

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