The diet-derived sulforaphane inhibits matrix metalloproteinase-9-activated human brain microvascular endothelial cell migration and tubulogenesis.
Human brain microvascular endothelial cells (HBMECs) play an essential role as structural and functional components of the blood-brain barrier (BBB). While disruption of the BBB by the brain tumor-secreted matrix metalloproteinase-9 (MMP-9) favors tumor invasion, the role and regulation of MMP-9 secretion by HBMEC themselves in response to carcinogens or brain tumor-derived growth factors has received little attention. Our study delineates a unique brain endothelial phenotype in that MMP-9 secretion is increased upon phorbol 12-myristate 13-acetate (PMA) treatment of HBMEC. Sulforaphane (SFN), an isothiocyanate present in broccoli which exhibits chemopreventive properties, selectively inhibited the secretion of MMP-9 but not that of MMP-2. The decrease in MMP-9 gene expression correlated with a decrease in the expression of the mRNA stabilizing factor HuR protein triggered by SFN. PMA-induced HBMEC migration was also antagonized by SFN. Silencing of the MMP-9 gene inhibited PMA-induced MMP-9 secretion, cell migration, and in vitro tubulogenesis on Matrigel. While SFN inhibited the chemoattractive abilities of brain tumor-derived growth factors, it failed to inhibit PMA-induced tubulogenesis. Our data are indicative of a selective role for SFN to inhibit MMP-9-activated, but not basal, HBMEC migration, and tubulogenesis whose actions could add to SFN's antitumor properties.
Annabi
Borhane
B
Laboratoire d'Oncologie Moléculaire, Département de Chimie, Centre BIOMED, Université du Québec à Montréal, Quebec, Canada.
Rojas-Sutterlin
Shanti
S
Laroche
Mathieu
M
Lachambre
Marie-Paule
MP
Moumdjian
Robert
R
Béliveau
Richard
R
D016588:Anticarcinogenic Agents / Q000008:administration & dosage*; D001812:Blood-Brain Barrier / Q000187:drug effects; D001921:Brain / Q000098:blood supply*; D001932:Brain Neoplasms / Q000098:blood supply; D001937:Brassica / Q000737:chemistry; D002196:Capillaries / Q000033:anatomy & histology; D002461:Cell Line, Transformed; D002465:Cell Movement / Q000187:drug effects; D004032:Diet; D042783:Endothelial Cells / Q000166:cytology / Q000502:physiology; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D017879:Isothiocyanates; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000502:physiology*; D061965:Matrix Metalloproteinase Inhibitors; D008833:Microcirculation / Q000166:cytology; D009389:Neovascularization, Pathologic; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013454:Sulfoxides; D013861:Thiocyanates / Q000008:administration & dosage*
D016588:Anticarcinogenic Agents; D017879:Isothiocyanates; D061965:Matrix Metalloproteinase Inhibitors; D013454:Sulfoxides; D013861:Thiocyanates; D020780:Matrix Metalloproteinase 9; C016766:sulforaphane