Abstract 295: The Role of 20-HETE in the Control of Prostate Cancer Tumor Vasculature

20-Hydroxyeicosatetraenoic acid (20-HETE) is a cytochrome P450-derived arachidonic acid metabolite endowed with vasoconstrictor. Recent reports documented that 20-HETE synthesis inhibitors decrease the growth of glioma and renal cell carcimona, and that urinary 20-HETE levels are significantly elevated in prostate cancer patients. These reports led us to investigate the role of 20-HETE in the regulation of blood flow to prostate cancer tumors. First, we compared 20-HETE levels in prostate cancer cell line-LNCaP and normal prostate epithelial cells. Cultured LNCaP cells produced high levels of 20-HETE (566±139 pg/mg protein), whereas 20-HETE production was undetectable in normal prostate epithelial cells. Second, subcutaneous tumors were induced in balb/c nude mice by injection of LNCaP cells, followed by assessment of 20-HETE in both tumors and isolated tumor vessels. We found that LNCaP cell-derived tumors had high levels of 20-HETE (425±97 pg/mg protein), while the level in isolated tumor vessels was undetectable. Third, we used laser-doppler flowmetry to evaluate whether tumor-derived 20-HETE influences tumor blood flow and vessel diameter in vivo. Topical application of the 20-HETE antagonist 20-6,15-HEDE (1 mM) to tumor vessels in vivo increased blood flow by 1.81±0.34-fold and vessel diameter by 1.286±0.133-fold, which responses were reversed by topical application of 20-HETE in a dose-dependent manner. We conclude that LNCaP cell-derived tumors produce 20-HETE which, in turn, promotes vasoconstriction leading to reduction of tumor blood flow.