Abstract
A growing number of studies have demonstrated that physiological factors can influence the progression of several cancers via cellular immune function, angiogenesis and metastasis. Recently, stress-induced catecholamines have been shown to increase the expression of various cancer progressive factors, including vascular endothelial growth factor (VEGF), matrix metalloproteinases and interleukins. However, a detailed mechanism remains to be identified. In this study, we investigated the role of adrenergic receptors and hypoxia-inducible factor (HIF)-1α protein in catecholamine-induced VEGF expression and angiogenesis. Treatment of the cells with norepinephrine (NE) or isoproterenol induced VEGF expression and HIF-1α protein amount in a dose-dependent manner. Induction of VEGF expression by NE was abrogated when the cells were transfected with HIF-1α-specific siRNA. Similarly, adenylate cyclase activator forskolin and cyclic AMP-dependent protein kinase A inhibitor H-89 enhanced and decreased HIF-1α protein amount, respectively. More importantly, conditioned medium of NE-stimulated cancer cells induced angiogenesis in a HIF-1α protein-dependent manner. In addition, pretreatment of cells with propranolol, a β-adrenergic receptor (AR) blocker, completely abolished induction of VEGF expression and HIF-1α protein amount by NE in all of the tested cancer cells. However, treatment with the α1-AR blocker prazosin inhibited NE-induced HIF-1α protein amount and angiogenesis in SK-Hep1 and PC-3 but not MDA-MB-231 cells. Collectively, our results suggest that ARs and HIF-1α protein have critical roles in NE-induced VEGF expression in cancer cells, leading to stimulation of angiogenesis. These findings will help to understand the mechanism of cancer progression by stress-induced catecholamines and design therapeutic strategies for cancer angiogenesis.
Original language | English (US) |
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Pages (from-to) | 2306-2316 |
Number of pages | 11 |
Journal | International Journal of Cancer |
Volume | 128 |
Issue number | 10 |
DOIs | |
State | Published - May 1 2011 |
Externally published | Yes |
Keywords
- adrenergic receptors
- angiogenesis
- hypoxia-inducible factor
- norepinephrine
- vascular endothelial growth factor
ASJC Scopus subject areas
- Oncology
- Cancer Research