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

作　　者：Heng-tong HU Qing-yong MA Dong ZHANG Su-gang SHEN Liang HAN Ya-dong MA Ruo-fei LI Ke-ping XIE 

机构地区：[1]Department of Hepatobiliary Surgery, The First Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an 710061, China [2]Department of Urinary Surgery, The Second Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an 710004, China [3]Department of Osteological Surgery, The Second Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an 710004, China [4]Department of Cancer Biology, University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030,USA

出　　处：《Acta Pharmacologica Sinica》2010年第1期102-110,共9页中国药理学报（英文版）

摘　　要：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.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.

关 键 词：β-adrenergic receptor epidermal growth factor receptor hypoxia-inducible factor-1α protein kinase A ERK1/2 Akt hypo-thalamic-pituitary-adrenal axis pancreatic cancer 

分 类 号：Q813[生物学—生物工程] S858.316.2[农业科学—临床兽医学]