TY - JOUR
T1 - Aryl-hydrocarbon receptor-dependent alteration of FAK/RhoA in the inhibition of HUVEC motility by 3-methylcholanthrene
AU - Chang, Chih Cheng
AU - Tsai, Shih Ying
AU - Lin, Heng
AU - Li, Hsiao Fen
AU - Lee, Yi Hsuan
AU - Chou, Ying
AU - Jen, Chih Yu
AU - Juan, Shu Hui
PY - 2009/10
Y1 - 2009/10
N2 - 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.
AB - 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.
KW - 3-Methylcholanthrene
KW - Adhesion
KW - Alpha-naphthoflavon (alpha-NF)
KW - Angiogenesis
KW - Aryl-hydrocarbon receptor
KW - Cell motility
KW - Focal adhesion kinase (FAK)
KW - Resveratrol
UR - http://www.scopus.com/inward/record.url?scp=70349308229&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=70349308229&partnerID=8YFLogxK
U2 - 10.1007/s00018-009-0102-7
DO - 10.1007/s00018-009-0102-7
M3 - Article
C2 - 19649566
AN - SCOPUS:70349308229
SN - 1420-682X
VL - 66
SP - 3193
EP - 3205
JO - Cellular and Molecular Life Sciences
JF - Cellular and Molecular Life Sciences
IS - 19
ER -