title: Norepinephrine induces VEGF expression and angiogenesis by a hypoxia-inducible factor-1α protein-dependent mechanism.
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.
authors: Department of Pharmacology, Myunggok Medical Research Institute, College of Medicine, Konyang University, Daejeon, Republic of Korea.
authors: Soon Young
authors: SY
authors: Park
authors: Joo Hee
authors: JH
authors: Kang
authors: Kang Jin
authors: KJ
authors: Jeong
authors: Jangsoon
authors: J
authors: Lee
authors: Jeong Whan
authors: JW
authors: Han
authors: Wahn Soo
authors: WS
authors: Choi
authors: Yong Kee
authors: YK
authors: Kim
authors: Jaeku
authors: J
authors: Kang
authors: Chang Gyo
authors: CG
authors: Park
authors: Hoi Young
authors: HY
authors: Lee
mesh_terms: D001483:Base Sequence; D045744:Cell Line, Tumor; D017931:DNA Primers; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D009389:Neovascularization, Pathologic / Q000139:chemically induced*; D009638:Norepinephrine / Q000494:pharmacology*; D016133:Polymerase Chain Reaction; D034741:RNA, Small Interfering; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics*
chemical_list: D017931:DNA Primers; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D034741:RNA, Small Interfering; D042461:Vascular Endothelial Growth Factor A; D009638:Norepinephrine