Journal
ONCOTARGETS AND THERAPY
Volume 3, Issue -, Pages 219-226Publisher
DOVE MEDICAL PRESS LTD
DOI: 10.2147/OTT.S14503
Keywords
medulloblastoma; beta-adrenergic receptors; MMP-9; NF-kappa B
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Funding
- Natural Sciences and Engineering Research Council of Canada (NSERC)
- Claude Bertrand Chair
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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 propranolol against a pediatric brain tumor-derived DAOY medulloblastoma cell model. Gene expression of beta(1)-, beta(2)-, and beta(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 (I kappa B), preventing the I kappa B phosphorylation which is a prerequisite for I kappa B degradation. Propranolol inhibition of I kappa B phosphorylation was shown to occur with optimal efficacy at 30 mu M. Although propranolol, at up to 100 mu M, 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 beta-adrenergic receptor signaling functions involving the nuclear factor-kappaB-mediated regulation of MMP-9.
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