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

Soon Young Park, Joo Hee Kang, Kang Jin Jeong, Jangsoon Lee, Jeong Whan Han, Wahn Soo Choi, Yong Kee Kim, Jaeku Kang, Chang Gyo Park, Hoi Young Lee

Research output: Contribution to journalArticlepeer-review

114 Scopus citations

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 languageEnglish (US)
Pages (from-to)2306-2316
Number of pages11
JournalInternational Journal of Cancer
Volume128
Issue number10
DOIs
StatePublished - May 1 2011
Externally publishedYes

Keywords

  • adrenergic receptors
  • angiogenesis
  • hypoxia-inducible factor
  • norepinephrine
  • vascular endothelial growth factor

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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