Original Article

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

Heng-tong Hu, Qing-yong Ma, Dong Zhang, Su-gang Shen, Liang Han, Ya-dong Ma, Ruo-fei Li, Ke-ping Xie
DOI: 10.1038/aps.2009.181


Aim: To examine whether β-adrenoceptor (β-AR) agonists can induce hypoxia-inducible factor (HIF)-1α 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 β-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 β-AR agonists led to accumulation of HIF-1α and then up-regulated expression of its target genes independently of oxygen levels. The induction was partly or completely inhibited not only by β-AR antagonists but also by inhibitors of PKA transduction pathways and by siHIF-1α. Both β1-AR and β2-AR agonists produced the above-mentioned effects, but β2-AR agonist was more potent.
Conclusion: Activation of β-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-1α and downstream target genes independently of oxygen level. Our data suggest a novel mechanism in pancreatic cancer cells that links β-AR and HIF-1α signaling under normoxic conditions, with implications for the control of glucose transport, angiogenesis and metastasis.

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