beta2-adrenergic antagonists suppress pancreatic cancer cell invasion by inhibiting CREB, NFkappaB and AP-1.

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Zhang D, Ma QY, Hu HT, Zhang M

beta2-adrenergic antagonists suppress pancreatic cancer cell invasion by inhibiting CREB, NFkappaB and AP-1.

Cancer Biol Ther. 2010 Jul 1;10(1):19-29.

PubMed ID
20424515 [ View in PubMed
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Abstract

Smoking and chronic stress are well-documented risk factors that are associated with beta-adrenoceptors in the development of pancreatic cancer. Stimulation of beta-adrenoceptors can activate cyclic adenosine monophosphate (cAMP)/ protein kinase A (PKA) and mitogen-activated protein kinase (MAPK) pathways in pancreatic cancer cells. Many recent studies have focused on the function of beta-adrenoceptors in cancer invasion. Thus, we hypothesized that beta-adrenoceptors may play a role in pancreatic cancer invasion, and beta-blockers may suppress the pancreatic cancer invasion and proliferation. MIA PaCa-2 and BxPC-3 cell lines express mRNA and protein of both beta1 and beta2-adrenoceptors. beta2-adrenergic antagonist ICI118,551 and beta1/2-adrenergic antagonist propranolol significantly suppressed cell invasion and proliferation in comparison to beta1-adrenergic antagonist metoprolol and control in a Matrigel invasion assay and subrenal capsular assay. Treatment with beta2-adrenoceptor antagonists inhibited activation of transcription factors nuclear factor kappaB (NF-kappaB), activator protein 1 (AP-1) and cAMP response element binding protein (CREB) as demonstrated by electrophoretic mobility shift assays and Western blotting. beta2-adrenoceptor antagonists also significantly altered vascular endothelial growth factor (VEGF), cyclooxygenase-2 (COX-2), matrix metalloproteinase 2 (MMP-2) and MMP-9 expression. The beta2-adrenergic antagonists suppressed invasion and proliferation by inhibiting both cAMP/PKA and Ras, which regulate activation of the MAPK pathway and transcription factors, such as NF-kappaB, AP-1 and CREB, as well as expression of its target genes, MMP-9, MMP-2 and VEGF. However, beta1-adrenergic antagonists suppressed invasion by inhibiting only the cAMP/PKA pathway, suggesting that they may be useful as novel preventive and therapeutic strategies for pancreatic cancer.