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

Abstract

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.

β2-Adrenergic Receptor Agonists Inhibit the Proliferation of 1321N1 Astrocytoma Cells

“…For example, activation of ␤ 2 -AR increased tumor angiogenesis and enhanced the expression of vascular endothelial growth factor and metalloproteinases in a mouse model of ovarian carcinoma through activation of the cAMP/PKA signaling pathway (Thaker et al, 2006). An association between ␤ 2 -AR agonism and the promotion of tumor growth has also been demonstrated in human hepatocellular carcinoma cells (Yuan et al, 2010), pancreatic cancer cells (Weddle et al, 2001;Hu et al, 2010), and gastric cancer cells (Shin et al, 2007).…”

Effect of mesenchymal stem cells on hypoxia-induced desensitization of β2-adrenergic receptors in rat osteosarcoma cells

“…Immune cells are involved in the hypothalamic-pituitaryadrenal axis and the sympathetic nervous system, through their expression of receptors for glucocorticoids and catecholamines, respectively (22). In addition, the direct effects of stress-related neurotransmitters have been reported in various types of cancer through β2AR signaling (9-13).…”

“…Neurotransmitters are significant in cancer progression (22). Immune cells are involved in the hypothalamic-pituitaryadrenal axis and the sympathetic nervous system, through their expression of receptors for glucocorticoids and catecholamines, respectively (22).…”

Recent Advances on the Role of G Protein-Coupled Receptors in Hypoxia-Mediated Signaling

“…Moreover, the adrenoreceptors have been shown to functionally interact with opioid receptors (43), which elicit protective actions in response to pre-and post-conditioning stimuli upon cardiac and cerebral damages (44,45). It is worth noting that certain ligand-activated GPCRs induce HIF-1 expression and function (46)(47)(48), thus mimicking hypoxic conditions. For instance, the recruitment of transcription factors to the promoter sequence of HIF-1 as well as the stabilization of HIF-1 protein levels may occur upon activation of GPCRs by endothelin-1 (ET-1), β-adrenoceptor agonists, and lysophosphatidic acid (46)(47)(48).…”

“…It is worth noting that certain ligand-activated GPCRs induce HIF-1 expression and function (46)(47)(48), thus mimicking hypoxic conditions. For instance, the recruitment of transcription factors to the promoter sequence of HIF-1 as well as the stabilization of HIF-1 protein levels may occur upon activation of GPCRs by endothelin-1 (ET-1), β-adrenoceptor agonists, and lysophosphatidic acid (46)(47)(48).…”