COX-2 and Prostate Cancer Angiogenesis

摘要

Cyclooxygenase-2 (COX-2) is an inducible enzyme which catalyzes the conversion of arachidonic acid to prostaglandins and has previously been demonstrated to play a role in carcinogenesis. We demonstrated that COX-2 and one of its major prostaglandin products, PGE2, are mediators of hypoxia-induced increases in a potent angiogenic factor, VEGF, in a human prostate cancer cell line. In these studies we determined (1) The optimal dosing and timing of administration of a cox-2 inhibitor (NS-398) in an animal model of prostate cancer (2) and (3) the mechanisms underlying the observed effects of COX-2 and PGE2 on hypoxia-induced upregulation of VEGF and tumor angiogenesis. Over the past year, we have completed our in vivo studies and determined that NS-398 inhibits prostate tumor growth significantly, whether it is given before or after tumor cell inoculation. We also completed our studies demonstrating that PGE2 induces the protein expression of a central regulator of hypoxic effects, hypoxia-inducible factor-1 alpha (HIF-1 alpha-1) and induces its nuclear localization. Our data indicates that NS-398 blocks hypoxic effects on HIF-1 alpha protein while PGE2 restores hypoxic effects, even in the presence of NS- 398. Several kinase pathways are involved in PGE2 effects on HIF-1 alpha protein stabilization.