HIF-1 alpha links beta-adrenoceptor agonists and pancreatic cancer cells under normoxic condition

Aim: To examine whether beta-adrenoceptor (beta-AR) agonists can induce hypoxia-inducible factor (HIF)-1 alpha 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 beta-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 beta-AR agonists led to accumulation of HIF-1 alpha 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-1 alpha. Both beta 1-AR and beta 2-AR agonists produced the above-mentioned effects, but beta 2-AR agonist was more potent. Conclusion: Activation of beta-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-1 alpha and downstream target genes independently of oxygen level. Our data suggest a novel mechanism in pancreatic cancer cells that links beta-AR and HIF-1 alpha signaling under normoxic conditions, with implications for the control of glucose transport, angiogenesis and metastasis.