Aryl-hydrocarbon receptor-dependent alteration of FAK/RhoA in the inhibition of HUVEC motility by 3-methylcholanthrene |
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| Authors: | Chih-Cheng Chang Shih-Ying Tsai Heng Lin Hsiao-Fen Li Yi-Hsuan Lee Ying Chou Chih-Yu Jen Shu-Hui Juan |
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| Institution: | (1) Department of Physiology, Graduate Institute of Medical Sciences, Taipei Medical University, 250 Wu-Hsing Street, Taipei, 110, Taiwan;(2) Department of Physiology, Taipei Medical University, Taipei, Taiwan;(3) Institute of Pharmacology and Toxicology, Tzu Chi University, Hualien, Taiwan;(4) Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan; |
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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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