title: Progesterone Inhibits Endothelial Cell Migration Through Suppression of the Rho Activity Mediated by cSrc Activation.
abstract: We previously showed that progesterone (P4) could inhibit the proliferation of human umbilical venous endothelial cells (HUVECs) through the p53-dependent pathway. In the present study, we further demonstrated that P4 at physiologic levels (5-500 nM) concentration-dependently inhibited migration of HUVECs. This effect was blocked by pre-treatment with the P4 receptor (PR) agonist-antagonist, RU486, suggesting that the P4-induced migration inhibition in HUVECs was through the PR-mediated signaling pathway. Western blot analyses demonstrated that the levels of RhoA and Rac-1 protein were reduced in the P4-treated HUVECs. P4 also inhibited the membrane translocation of RhoA and Rac-1 protein. Moreover, the P4-induced migration inhibition in HUVECs was prevented by over-expression of the constitutively active RhoA construct (RhoA V14). However, pre-treatment with the ROCK (a kinase associated with RhoA for transducing RhoA signaling) inhibitor, Y27632, abolished the over-expression of RhoA-induced prevention effect on the P4-induced migration inhibition in HUVECs. These data suggest that the inhibition of Rho GTPases might account for the P4-induced migration inhibition of HUVECs. Pre-treatment with the cSrc inhibitor, PP2, prevented the P4-induced migration inhibition in HUVEC. The levels of phosphorylated focal adhesion kinase (FAK) and paxillin protein were also decreased by P4 treatment. Taken together, these results suggest that suppression of the Rho-mediated pathway might be involved in the signal transduction leading to the inhibition of cell migration caused by P4 in HUVECs.
authors.affiliation: Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan.|Department of Ophthalmology, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan.
authors.forename: Tong-Sheng
authors.initials: TS
authors.lastname: Lee
authors.affiliation: Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan.
authors.forename: Jhen-Jhe
authors.initials: JJ
authors.lastname: Lin
authors.affiliation: Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan.
authors.forename: Yen-Nien
authors.initials: YN
authors.lastname: Huo
authors.affiliation: Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan.|Department of Physiology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.|Cancer Research Center, Taipei Medical University Hospital, Taipei, Taiwan.
authors.forename: Wen-Sen
authors.initials: WS
authors.lastname: Lee
mesh_terms: D002465:Cell Movement / Q000187:drug effects; D015536:Down-Regulation; D006727:Hormone Antagonists / Q000494:pharmacology; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects*; D006801:Humans; D015735:Mifepristone / Q000494:pharmacology; D011374:Progesterone / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: C412373:AG 1879; D006727:Hormone Antagonists; D011743:Pyrimidines; C107953:RAC1 protein, human; C066737:RHOA protein, human; D015735:Mifepristone; D011374:Progesterone; D019061:src-Family Kinases; D020830:rac1 GTP-Binding Protein; D020742:rhoA GTP-Binding Protein
keywords: ANGIOGENESIS; PROGESTERONE RECEPTOR; RHO PROTEINS