Hypoxia up-regulates the effects of prostaglandin E2 on tumor angiogenesis in ovarian cancer cells.

OBJECTIVE: Emerging evidence supports a role for prostaglandins (PG) and their synthesizing enzyme, cyclooxygenase (COX), in tumor angiogenesis. The objective of this study was to investigate the effects of prostaglandin E(2) (PGE(2)) on the expression of vascular endothelial growth factor (VEGF) and hypoxia-inducible transcription factor-1 alpha (HIF-1alpha) genes in epithelial ovarian cancer (EOC) cells.

METHODS: Two human EOC cell lines, MDAH-2774 and SKOV-3, were treated with exogenous dimethyl prostaglandin E(2) (dmPGE(2)) at two doses of 10 and 50 microg/ml and cultured for 24 h under both normoxic and hypoxic conditions. Total RNA was extracted from EOC cells with the use of a monophasic solution of phenol and GITC/Trizol method. The levels of COX-2, VEGF, and HIF-1alpha mRNA were measured by quantitative reverse transcription PCR (RT-PCR).

RESULTS: Under normoxic conditions, treatment of both ovarian cancer cell lines with dmPGE(2) resulted in a significant increase in VEGF expression but had no effect on HIF-1alpha. Culturing the cells under hypoxic conditions resulted in an increase in HIF-1alpha and VEGF mRNAs. The combination of hypoxia and dmPGE(2) treatment resulted in the highest levels of VEGF and HIF-1alpha when compared to either individual treatment.

CONCLUSION: PGE(2) is a potent stimulator of VEGF expression in ovarian cancer cells. This effect of PG is further potentiated under hypoxic conditions where it is also associated with a significant increase in HIF-1alpha expression.