Pharmacological targeting of β-adrenergic receptor functions abrogates NF-κB signaling and MMP-9 secretion in medulloblastoma cells.
Targeting of the vascular endothelium compartment explains, in part, the therapeutic efficacy of the nonselective β-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 propranolol against a pediatric brain tumor- derived DAOY medulloblastoma cell model. Gene expression of β(1)-, β(2)-, and β(3)-adrenergic receptors was confirmed in 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) by phorbol 12-myristate 13-acetate (PMA). Propranolol not only inhibited PMA- induced phosphorylation of the extracellular signal-regulated kinase (Erk), but also that of IkappaB (IκB), preventing the IκB phosphorylation which is a prerequisite for IκB degradation. Propranolol inhibition of IκB phosphorylation was shown to occur with optimal efficacy at 30 μM. Although propranolol, at up to 100 μM, did not affect cell viability, it potentiated PMA- mediated signaling that ultimately led to diminished phosphorylation of Akt. The anti-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 β-adrenergic receptor signaling functions involving the nuclear factor-kappaB-mediated regulation of MMP-9.
Laboratoire d'Oncologie Moléculaire, Département de Chimie, Centre de Recherche BioMED.
Borhane
B
Annabi
Eric
E
Vaillancourt-Jean
Alexander G
AG
Weil
Richard
R
Béliveau