Norepinephrine induces VEGF expression and angiogenesis by a hypoxia-inducible factor-1α protein-dependent mechanism

• Published in: International journal of cancer 2011-05, Vol.128 (10), p.2306-2316
• Main Authors: SOON YOUNG PARK, JOO HEE KANG, KANG JIN JEONG, LEE, Jangsoon, JEONG WHAN HAN, WAHN SOO CHOI, YONG KEE KIM, KANG, Jaeku, CHANG GYO PARK, HOI YOUNG LEE
• Format: Article
• Language: English
• Subjects: Base Sequence; Biological and medical sciences; Cell Line, Tumor; DNA Primers; Enzyme-Linked Immunosorbent Assay; Humans; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Medical sciences; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Neovascularization, Pathologic - chemically induced; Norepinephrine - pharmacology; Polymerase Chain Reaction; RNA, Small Interfering; Tumors; Vascular Endothelial Growth Factor A - genetics
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.25589

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.