Tumor-growth-promoting cyclooxygenase-2 prostaglandin E2 pathway provides medulloblastoma therapeutic targets

Abstract

Prostaglandin E2 (PGE2) has been shown to play important roles in several aspects of tumor development and progression. PGE2 is synthesized from arachidonic acid by cyclooxygenases (COX) and prostaglandin E synthases (PGES) and mediates its biological activity through binding to the four prostanoid receptors EP1 through EP 4. In this study, we show for the first time that medulloblas-toma (MB), the most common malignant childhood brain tumor, expresses high levels of COX-2, microsomal prostaglandin E synthase-1, and EP1 through EP 4 and secretes PGE2. PGE2 and the EP2 receptor agonist butaprost stimulated MB cell proliferation. Treatment of MB cells with COX inhibitors suppressed PGE2 production and induced caspase-dependent apoptosis. Similarly, specific COX-2 silencing by small interfering RNA inhibited MB cell growth. EP1 and EP3 receptor antagonists ONO-8713 and ONO-AE3-240, but not the EP4 antagonists ONO-AE3-208 and AH 23848, inhibited tumor cell proliferation, indicating the significance of EP1 and EP3 but not EP 4 for MB growth. Administration of COX inhibitors at clinically achievable nontoxic concentrations significantly inhibited growth of established human MB xenografts. Apoptosis was increased, proliferation was reduced, and angiogenesis was inhibited in MBs treated with COX inhibitors. This study suggests that PGE2 is important for MB growth and that therapies targeting the prostanoid metabolic pathway are potentially beneficial and should be tested in clinical settings for treatment of children with MB. Copyright 2008 by the Society.