COX-2 and Prostate Cancer Angiogenesis
Abstract
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 are determining (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 extended our in vivo studies to determine the optimal timing of administration of NS-398 in the in vivo model system. We demonstrated that PGE2 induces the protein expression of a central regulator of hypoxic effects, hypoxia-inducible factor-alpha (HIF-alpha) and induces its nuclear localization. Our data indicates that NS-398 blocks hypoxic effects on HIF-alpha protein while PGE2 restores hypoxic effects, even in the presence of NS- 398. Finally, we demonstrated that several kinase pathways, most notably the MAP kinase pathway, are involved in PGE2 effects on HIP-alpha protein stabilization.
Document Details
- Document Type
- Technical Report
- Publication Date
- Mar 01, 2002
- Accession Number
- ADA405593
Entities
People
- Alice C. Levine
Organizations
- Icahn School of Medicine at Mount Sinai