beta-Adrenergic growth regulation of human cancer cell lines derived from pancreatic ductal carcinomas

Abstract

Exocrine ductal carcinoma of the pancreas has been associated with smoking, and the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) causes this cancer type in laboratory rodents. Current knowledge on the growth regulation of this malignancy is extremely limited. Recent studies have shown overexpression of cyclooxygenase 2 (COX 2) and 5-lipoxygenase (5-lipox) in exocrine pancreatic carcinomas, suggesting a potential role of the arachidonic acid (AA) cascade in the regulation of this cancer type. In support of this interpretation, our data show high basal levels of AA release in two human cell lines derived from exocrine ductal pancreatic carcinomas. Both cell lines expressed m-RNA for beta2-adrenergic receptors and beta1-adrenergic receptors. Radio-receptor assays showed that beta2-adrenergic receptors predominated over beta1-adrenergic receptors. beta2-Adrenergic antagonist ICI118,551 significantly reduced basal AA release and DNA synthesis when the cells were maintained in complete medium. DNA synthesis of the cell line (Panc-1) with an activating point mutation in codon 12 of the ki-ras gene was significantly stimulated by NNK when cells were maintained in complete medium and this response was inhibited by the beta-blocker ICI118,551, the COX-inhibitor aspirin, or the 5-lipox-inhibitor MK-886. The cell line without ras mutations (BXPC-3) did not show a significant response to NNK in complete medium. When the assays were conducted in serum-free medium, both cell lines demonstrated increased DNA synthesis in response to NNK, an effect inhibited by the beta2-blocker, aspirin, or MK-886. Panc-1 cells were more sensitive to the stimulating effects of NNK and less responsive to the inhibitors than BXPC-3 cells. Our findings are in accord with a recent report which has identified NNK as a beta-adrenergic agonist and suggest beta-adrenergic, AA-dependent regulatory pathways in pancreatic cancer as a novel target for cancer intervention strategies.

The mitogenic effectors of isoproterenol in human hepatocellular carcinoma cells

“…4A and B). The ß2-AR signaling was confirmed using ICI 118551, the specificity of the phosphorylation of ERK1/2 was confirmed using U0126, and the possible involvement of EGFR was ruled out using PD153035 (17)(18)(19). ISO-induced phosphorylation of ERK1/2 was effectively inhibited either by ICI 118551 (5 μM) or U0126 (10 μM), but not by PD153035 (25 μM).…”

“…It has been demonstrated that the most frequently associated signaling pathways that downstream ß2-AR (G-protein-coupled receptor) are the adenyl cyclase/cyclic adenosine monophospatedependent protein kinase (cAMP/PKA), mitogen activated protein kinase/extracellular signal-regulated kinase 1/2 (MAPK/ERK1/2) and phosphatidylinositol-3-kinase/ AKT or protein kinase B (PI3K/AKT) signaling pathways (2,(17)(18)(19). We used the selective ß2-AR antagonist ICI 118551 to confirm the ß2-AR signaling, and the PKA inhibitor H-89, the MEK-specific inhibitor U0126, the PI3K inhibitor LY294002 and the specific EGFR tyrosine kinase inhibitor PD153035 to rule out the possible involvement of these signaling pathways in mediating the effect of ISO.…”

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

“…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] .…”

Beta-adrenergic signaling, a novel target for cancer therapy?

“…In addition, chronic nicotine-induced progression of xenografts from a human lung adenocarcinoma cell line was associated with increased systemic levels of stress neurotransmitters and upregulation of nAChRs, cAMP, p-CREB and p-ERK in the tumor cells while treatment of the mice with GABA inhibited all of these responses. In analogy to these findings, it was also shown that cell lines from pancreatic ductal adenocarcinomas were stimulated in their growth via NNK or isoproterenol-induced β-AR signaling [23] and that the beta-blocker propranol inhibited the development of NNK-induced pancreatic cancer in hamsters [24] while inducing apoptosis in pancreatic cancer cells in vitro [25]. Moreover, nicotine induced significant progression of pancreatic cancer xenograft growth that was associated with a significant systemic increase in stress neurotransmitters and upregulation of cAMP p-CREB and p-ERK in xenograft tissues.…”