期刊
CANCER BIOLOGY & THERAPY
卷 10, 期 1, 页码 19-29出版社
LANDES BIOSCIENCE
DOI: 10.4161/cbt.10.1.11944
关键词
beta(2)-adrenergic antagonists; invasion; pancreatic cancer cell; CREB; NF kappa B; AP-1; Ras
类别
资金
- National Natural Science Foundation of China [30700817]
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 beta(1) and beta(2)-adrenoceptors. beta(2)-adrenergic antagonist IC111B(t)551 and beta(1/2)-adrenergicantagonist propranolol significantly suppressed cell invasion and proliferation in comparison to beta(1)-adrenergic antagonist metoprolol and control in a Matrigel invasion assay and subrenal capsular assay. Treatment with beta(2)-adrenoceptor antagonists inhibited activation of transcription factors nuclear factor kappa B (NF kappa B), activator protein 1 (AP-1) and cAMP response element binding protein (CREB) as demonstrated by electrophoretic mobility shift assays and western blotting. beta(2)-adrenoceptor antagonists also significantly altered vascular endothelial growth factor (VEGF), cyclooxygenase-2 (COX-2), matrix metalloproteinase 2 (MMP-2) and MMP-9 expression. The beta(2)-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 kappa B, AP-1 and CREB, as well as expression of its target genes, MMP-9, MMP-2 and VEGF. However, beta(1)-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.
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