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Smoking and chronic stress are well-documented risk factors that are associated with β-adrenoceptors in the development of pancreatic cancer. Stimulation of β-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 β-adrenoceptors in cancer invasion. Thus, we hypothesized that β-adrenoceptors may play a role in pancreatic cancer invasion, and β-blockers may suppress the pancreatic cancer invasion and proliferation. MIA PaCa-2 and BxPC-3 cell lines express mRNA and protein of both β1 and β2-adrenoceptors. β2-adrenergic antagonist ICI118,551 and β1/2-adrenergic antagonist propranolol significantly suppressed cell invasion and proliferation in comparison to β1-adrenergic antagonist metoprolol and control in a Matrigel invasion assay and subrenal capsular assay. Treatment with β2-adrenoceptor antagonists inhibited activation of transcription factors nuclear factor κB (NF-κB), activator protein 1 (AP-1) and cAMP response element binding protein (CREB) as demonstrated by electrophoretic mobility shift assays and Western blotting. β2-adrenoceptor antagonists also significantly altered vascular endothelial growth factor (VEGF), cyclooxygenase-2 (COX-2), matrix metalloproteinase 2 (MMP-2) and MMP-9 expression. The β2-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-κB, AP-1 and CREB, as well as expression of its target genes, MMP-9, MMP-2 and VEGF. However, β1-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.

To examine whether beta-adrenoceptor (beta-AR) agonists can induce hypoxia-inducible factor (HIF)-1alpha accumulation which then up-regulate the expression of its target genes in pancreatic cancer cells at normoxia, and to further elucidate the mechanism involved.Pulse-chase assay, RT-PCR, and Western blot were employed to detect the effects of beta-AR agonists and antagonists, siRNA as well as several inhibitors of signal transduction pathways on MIA PaCa2 and BxPC-3 pancreatic cancer cells.Treatment of pancreatic cancer cell lines with beta-AR agonists led to accumulation of HIF-1alpha and then up-regulated expression of its target genes independently of oxygen levels. The induction was partly or completely inhibited not only by beta-AR antagonists but also by inhibitors of PKA transduction pathways and by siHIF-1alpha. Both beta1-AR and beta2-AR agonists produced the above-mentioned effects, but beta2-AR agonist was more potent.Activation of beta-AR receptor transactivates epidermal growth factor receptor (EGFR) and then elicits Akt and ERK1/2 in a PKA-dependent manner, which together up-regulate levels of HIF-1alpha and downstream target genes independently of oxygen level. Our data suggest a novel mechanism in pancreatic cancer cells that links beta-AR and HIF-1alpha signaling under normoxic conditions, with implications for the control of glucose transport, angiogenesis and metastasis.

AIM: To study the variabilities of serum proteomic spectra in patients with gastric cancer before and after operation in order to detect the specific protein markers that can be used for quick diagnosis of gastric cancer. METHODS: Proteomic spectra of 46 serum samples from patients with gastric cancer before and after operation and 40 from normal individuals were generated by IMAC-Cu protein chip and surface-enhanced laser desorption/ ionization time of flight mass spectrometry. RESULTS: Fourteen differentially expressed proteins in serum were screened by analysis of proteomic spectra of preoperative patients and normal individuals. We obtained 4 proteins (heat shock protein 27, glucose-regulated protein, prohibitin, protein disulfide isomerase A3) making up marker pattern which was able to class the patient-team and normal-team. These marker patterns yielded 95.7% sensitivity and 92.5% specificity, respectively. The proteins over-expressed in serum of preoperative patients were obviously down-regulated. CONCLUSION: Specific protein markers of gastric cancer can be used for the quick diagnosis of gastric cancer and judgment of prognosis. SELDI-TOF-MS is a useful tool for the detection and identification of new protein markers in serum.