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

• Published in: Acta pharmacologica Sinica 2010-01, Vol.31 (1), p.102-110
• 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: Article
• Language: English
• Subjects: Biomedical and Life Sciences; Biomedicine; Immunology; Internal Medicine; Medical Microbiology; Original; original-article; Pharmacology/Toxicology; Vaccine; β-肾上腺素受体; β2受体激动剂; 信号转导通路; 癌细胞; 缺氧诱导因子-1α; 肾上腺素受体激动剂; 胰腺癌; 表皮生长因子受体
• ISSN: 1671-4083; 1745-7254
• 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 impli- cations for the control of glucose transport, angiogenesis and metastasis.