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Aryl-hydrocarbon receptor-dependent alteration of FAK/RhoA in the inhibition of HUVEC motility by 3-methylcholanthrene

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Abstract

We previously demonstrated the antiproliferative and antiangiogenic effects of 3-methylcholanthrene (3MC), an aryl-hydrocarbon receptor (AhR) agonist, in human umbilical vascular endothelial cells (HUVECs). Herein, we unraveled its molecular mechanisms in inhibiting HUVEC motility. 3MC down-regulated FAK, but up-regulated RhoA, which was rescued by AhR knockdown. It led us to identify novel AhR binding sites in the FAK/RhoA promoters. Additionally, 3MC increased RhoA activity via suppression of a negative feedback pathway of FAK/p190RhoGAP. With an increase in membrane-bound RhoA, subsequent stress fiber and focal adhesion complex formation was observed in 3MC-treated cells, and this was reversed by a RhoA inhibitor and AhR antagonists. Notably, these compounds significantly reversed 3MC-mediated anti-migration in a transwell assay. The in vitro findings were further confirmed using an animal model of Matrigel formation in Balb/c mice. Collectively, AhR’s genomic regulation of FAK/RhoA, together with RhoA activation, is ascribable to the anti-migration effect of 3MC in HUVECs.

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Acknowledgment

This study was supported by a grant [NSC97-2320-B-038-017-MY3(1-3)] from the National Science Council, Taiwan.

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Authors and Affiliations

  1. Department of Physiology, Graduate Institute of Medical Sciences, Taipei Medical University, 250 Wu-Hsing Street, Taipei, 110, Taiwan

    Chih-Cheng Chang, Shih-Ying Tsai, Yi-Hsuan Lee, Ying Chou, Chih-Yu Jen & Shu-Hui Juan

  2. Department of Physiology, Taipei Medical University, Taipei, Taiwan

    Chih-Cheng Chang, Shih-Ying Tsai, Yi-Hsuan Lee, Ying Chou, Chih-Yu Jen & Shu-Hui Juan

  3. Institute of Pharmacology and Toxicology, Tzu Chi University, Hualien, Taiwan

    Heng Lin

  4. Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan

    Hsiao-Fen Li

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  1. Chih-Cheng Chang
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Correspondence to Shu-Hui Juan.

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Chang, CC., Tsai, SY., Lin, H. et al. Aryl-hydrocarbon receptor-dependent alteration of FAK/RhoA in the inhibition of HUVEC motility by 3-methylcholanthrene. Cell. Mol. Life Sci. 66, 3193–3205 (2009). https://doi.org/10.1007/s00018-009-0102-7

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  • DOI: https://doi.org/10.1007/s00018-009-0102-7

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