4318

MMP9

CLG4B|GELB|MANDP2|MMP-9;matrix metallopeptidase 9 (gelatinase B, 92kDa gelatinase, 92kDa type IV collagenase);MMP9;matrix metallopeptidase 9 (gelatinase B, 92kDa gelatinase, 92kDa type IV collagenase)

92 kDa gelatinase|92 kDa type IV collagenase|macrophage gelatinase|matrix metalloproteinase 9 (gelatinase B, 92kDa gelatinase, 92kDa type IV collagenase)|matrix metalloproteinase-9|type V collagenase

20q11.2-q13.1

protein-coding

Targeting of the vascular endothelium compartment explains, in part, the therapeutic efficacy of the nonselective beta-adrenergic antagonist propranolol against common endothelial tumors such as hemangiomas. In vitro, the antiangiogenic biological activity of propranolol was shown to inhibit human brain microvascular endothelial cell tubulogenesis. However, possible interference of propranolol with cell signaling associated with the tumoral compartment remains unexplored. We therefore assessed the potency of propranololagainst a pediatric brain tumor- derived DAOY medulloblastoma cell model. Gene expression of beta(1)-, beta(2)-, and beta(3)-adrenergic receptors was confirmedin DAOY cells by semiquantitative RT-PCR. We next found that propranolol dose-dependently inhibited induction of the key extracellular matrix-degrading and blood-brain barrier disrupting enzyme matrix metalloproteinase- 9 (MMP-9) byphorbol 12-myristate 13-acetate (PMA). Propranolol not only inhibited PMA- induced phosphorylation of the extracellular signal-regulated kinase (Erk), but also that of IkappaB (IkappaB), preventing the IkappaB phosphorylation which is a prerequisite for IkappaB degradation. Propranolol inhibition of IkappaB phosphorylation was shown to occur with optimal efficacy at 30 muM. Although propranolol, at up to 100 muM, did not affect cell viability, it potentiated PMA- mediated signaling that ultimately led to diminished phosphorylation of Akt. Theanti-Erk and anti-Akt phosphorylation effects are both suggestive of antiproliferative and antisurvival signaling, respectively. Our data are therefore indicative of a pharmacological role for propranolol against beta-adrenergic receptor signaling functions involving the nuclear factor-kappaB-mediated regulation of MMP-9.