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Essential role of PI-3K, ERKs and calcium signal pathways in nickel-induced VEGF expression

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Abstract

Exposure to a highly nickel-polluted environment has the potential to cause a variety of adverse health effects, such as the respiratory tract cancers. Since numerous studies have demonstrated that nickel generally has weak mutagenic activity, research focus had turned to cell signalling activation leading to gene modulation and epigenetic changes as a plausible mechanism of carcinogenesis. Previous studies have revealed that nickel compounds can induce the expression of vascular endothelial growth factor (VEGF), which is a key mediator of angiogenesis both in physiological and pathologic conditions. In the present study, we investigated the potential roles of PI-3K, ERKs, p38 kinase and calcium signalling in VEGF induction by nickel in Cl 41 cells. Exposure of Cl 41 cells to nickel compounds led to VEGF induction in both time- and dose-dependent manners. Pre-treatment of Cl 41 cells with PI-3K inhibitor, wortmannin or Ly294002, resulted in a striking inhibition of VEGF induction by nickel compounds, implicating the role of PI-3K in the induction. However, mTOR, one of downstream molecules of PI-3K, may not contribute to the induction because pre-treatment of Cl 41 cells with its inhibitor, rapamycin, did not show obvious decrease in nickel-induced VEGF expression. Furthermore, pre-treatment of Cl 41 cells with MEK1/2-ERKs pathway inhibitor, PD98059, significantly inhibited VEGF induction by both NiCl2 and Ni3S2, whereas p38 kinase inhibitor, SB202190, did not impair the induction. Pre-treatment of Cl 41 cells with intracellular calcium chelator, but not calcium channel blocker, inhibited VEGF induction by nickel. Collectively these data demonstrate that PI-3K, ERKs and cytosolic calcium, but not p38 kinase, play essential roles in VEGF induction by nickel compounds.

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Abbreviations

DMSO:

dimethyl sulfoxide

ERK:

extracellular signal–regulated kinases

FBS:

fetal bovine serum

HIF-1:

hypoxia-inducible Factor-1

JNK:

c-Jun N-terminal kinase

MAPK:

mitogen-activated protein kinase

MEM:

Eagle's minimal essential medium

mTOR:

mammalian target of rapamycin

PI-3K:

phosphotidylinositol 3-kinas

TGF-β1:

transforming growth factor beta 1

TPA:

12-O-tetradecanoylphorbol-13-acetate

VEGF:

vascular endothelial growth factor

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Authors and Affiliations

  1. Nelson Institute of Environmental Medicine, School of Medicine, New York University, New York, Tuxedo, USA

    Weiming Ouyang, Jingxia Li, Xianglin Shi, Max Costa & Chuanshu Huang

  2. Nelson Institute of Environmental Medicine, School of Medicine, New York University, 57 Old Forge Road, Tuxedo, NY, 10987, USA

    Chuanshu Huang

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  1. Weiming Ouyang
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  2. Jingxia Li
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  3. Xianglin Shi
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  4. Max Costa
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  5. Chuanshu Huang
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Correspondence to Chuanshu Huang.

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The first two authors have contributed equally to this work.

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Ouyang, W., Li, J., Shi, X. et al. Essential role of PI-3K, ERKs and calcium signal pathways in nickel-induced VEGF expression. Mol Cell Biochem 279, 35–43 (2005). https://doi.org/10.1007/s11010-005-8214-3

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