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

Authors

  • Soon Young Park,

    1. Department of Pharmacology, Myunggok Medical Research Institute, College of Medicine, Konyang University, Daejeon, Republic of Korea
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    • S.Y.P. and J.H.K. authors contributed equally to this work.

  • Joo Hee Kang,

    1. Department of Pharmacology, Myunggok Medical Research Institute, College of Medicine, Konyang University, Daejeon, Republic of Korea
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    • S.Y.P. and J.H.K. authors contributed equally to this work.

  • Kang Jin Jeong,

    1. Department of Pharmacology, Myunggok Medical Research Institute, College of Medicine, Konyang University, Daejeon, Republic of Korea
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  • Jangsoon Lee,

    1. Department of Breast Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
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  • Jeong Whan Han,

    1. Department of Biochemistry and Molecular Biology, College of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea
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  • Wahn Soo Choi,

    1. Department of Immunology, College of Medicine, Konkuk University, Chungju, Republic of Korea
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  • Yong Kee Kim,

    1. Department of Pharmacology, College of Medicine, Kwandong University, Gangneung, Republic of Korea
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  • Jaeku Kang,

    1. Department of Pharmacology, Myunggok Medical Research Institute, College of Medicine, Konyang University, Daejeon, Republic of Korea
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  • Chang Gyo Park,

    1. Department of Pharmacology, Myunggok Medical Research Institute, College of Medicine, Konyang University, Daejeon, Republic of Korea
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  • Hoi Young Lee

    Corresponding author
    1. Department of Pharmacology, Myunggok Medical Research Institute, College of Medicine, Konyang University, Daejeon, Republic of Korea
    • Department of Pharmacology, College of Medicine, Konyang University, 821 Medical Science Building, 685 Gasuwondong, Seo-gu, Daejeon 302-718, Republic of Korea
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    • Tel: +8242-600-6413, Fax: +8242-541-4626


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.

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