Prostaglandin E(2) (
PGE(2)) has been shown to play important roles in several aspects of
tumor development and progression.
PGE(2) 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 EP(1) through EP(4). In this study, we show for the first time that
medulloblastoma (MB), the most common malignant childhood
brain tumor, expresses high levels of COX-2, microsomal
prostaglandin E synthase-1, and EP(1) through EP(4) and secretes
PGE(2).
PGE(2) and the EP(2) receptor agonist
butaprost stimulated MB cell proliferation. Treatment of MB cells with COX inhibitors suppressed
PGE(2) production and induced caspase-dependent apoptosis. Similarly, specific COX-2 silencing by
small interfering RNA inhibited MB cell growth. EP(1) and EP(3) receptor antagonists
ONO-8713 and
ONO-AE3-240, but not the EP(4) antagonists
ONO-AE3-208 and
AH 23848, inhibited
tumor cell proliferation, indicating the significance of EP(1) and EP(3) 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
PGE(2) 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.