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

• Published in: Acta pharmacologica Sinica Vol. 31; no. 1; p. 102
• Main Authors: Hu, Heng-tong, Ma, Qing-yong, Zhang, Dong, Shen, Su-gang, Han, Liang, Ma, Ya-dong, Li, Ruo-fei, Xie, Ke-ping
• Format: Journal Article
• Language: English
• Published: United States 01.01.2010
• Subjects: Adrenergic beta-1 Receptor Agonists; Adrenergic beta-2 Receptor Agonists; Adrenergic beta-Agonists - pharmacology; Blotting, Western; Cell Line, Tumor; Cyclic AMP-Dependent Protein Kinases - metabolism; Humans; Hypoxia-Inducible Factor 1, alpha Subunit - drug effects; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3 - metabolism; Pancreatic Neoplasms - metabolism; Proto-Oncogene Proteins c-akt - metabolism; Receptor, Epidermal Growth Factor - metabolism; Reverse Transcriptase Polymerase Chain Reaction; RNA, Small Interfering - metabolism; Signal Transduction - drug effects; Up-Regulation - drug effects
• ISSN: 1745-7254
• DOI: 10.1038/aps.2009.181

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.