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Intracellular signaling pathways involved in cell growth inhibition of human umbilical vein endothelial cells by melatonin

Authors

  • Peilin Cui,

    1. Beijing Tiantan Hospital, Capital University of Medical Sciences & Chinese Academy of Medical Sciences, Beijing, China
    2. Institute of Microcirculation, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
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  • Minghua Yu,

    1. Institute of Microcirculation, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
    2. Institute of Basic Medical Sciences, Yunyang Medical College, Shiyan, China
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  • Zhaohua Luo,

    1. Institute of Microcirculation, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
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  • Ming Dai,

    1. Institute of Microcirculation, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
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  • Jianqun Han,

    1. Institute of Microcirculation, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
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  • Ruijuan Xiu,

    1. Institute of Microcirculation, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
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  • Zhaoxu Yang

    1. Beijing Tiantan Hospital, Capital University of Medical Sciences & Chinese Academy of Medical Sciences, Beijing, China
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Address reprint requests to Peilin Cui, Beijing Tiantan Hospital, Capital University of Medical Sciences, Chinese Academy of Medical Sciences, 6 Tiantan Xi Li, Beijing 100050, China.
E-mail: cplin1@yahoo.com.cn

Abstract

Abstract:  Melatonin, an indolamine mainly produced in the pineal gland, has received a great deal of attention in the last decade because of its oncostatic effects, which are due to its immunomodulatory, antiproliferative, antioxidant and its possible antiangiogenesis properties. Herein, we document its antiproliferative action on human umbilical vein endothelial cells (HUVECs). Moreover, the possible cell signaling pathways when melatonin inhibited HUVEC proliferation were explored in this study. Primary HUVECs were isolated, cultured, purified and identified before the studies were performed. HUVECs were found to possess G-protein-coupled membrane receptors for melatonin (MT1 and MT2) and also nuclear melatonin receptors (RORα and RORβ, especially RORβ). No obvious expression of RORγ was found. We investigated the membrane receptors and several intracellular signaling pathways including mitogen-activated protein kinases (MAPK)/extracellular signal-related kinases (ERK), phosphoinositol-3-kinase (PI3K)/Akt and protein kinases C (PKC) involved in antiproliferative action of melatonin on HUVECs. The blockade of these pathways using special inhibitors decreased cell growth. Furthermore, the constitutive activation of nuclear factor kappa B (NF-κB) contributed to the proliferation of HUVECs. High concentrations of melatonin inhibited both NF-κB expression and its binding ability to DNA, possibly through inactivation of ERK/Akt /PKC pathways. Taken together, high concentrations of melatonin markedly reduced HUVEC proliferation; the antiproliferative action of melatonin was closely correlated with following pathway: melatonin receptors/ERK/PI3K/Akt/PKC/ NF-κB.

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