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, VEGE, in a human prostate cancer cell line. In these studies we are determining (1) the optimal dosing and timing of a COX-2 inhibitor (NS398) in an animal model of human prostate cancer, (2)and (3) the mechanisms underlying the observed effects of COx-2 and PGE2 on hypoxia-induced upregulation of VEGE and tumor angiogenesis. Over the past year we have determined the optimal dose of NS398 in the in vivo model. We have also demonstrated that true hypoxia (as opposed to cobalt-chloride simulated hypoxia)induces VEGE expression in PC-3 ML prostate cancer cells and that NS398 prevents this effect while PGE2 restores it, Our studies demonstrate that PGE2 does increase the transcription of hypoxia-inducible factor-Lalpha (HIF-lalpha) but does increase HIF-lalpha protein expression, primarily in the cytoplasm. In the next two years, we will determine the optimal timing of Ns398 administration and determine how PGE2 increases HIF-lalpha protein and VEGE expression.
Document Details
- Document Type
- Technical Report
- Publication Date
- Mar 01, 2001
- Accession Number
- ADA392385
Entities
People
- Alice C. Levine
Organizations
- Icahn School of Medicine at Mount Sinai