Upregulation of vascular endothelial growth factor by cobalt chloride- simulated hypoxia is mediated by persistent induction of cyclooxygenase-2 in a metastatic human prostate cancer cell line

Xin Hua Liu, Alexander Kirschenbaum, Shen Yao, Mark E. Stearns, James F. Holland, Kevin Claffey, Alice C. Levine

Research output: Contribution to journalArticlepeer-review

153 Scopus citations

Abstract

Upregulation of vascular endothelial growth factor (VEGF) expression induced by hypoxia is crucial event leading to neovascularization. Cyclooxygenase-2, an inducible enzyme that catalyzes the formation of prostaglandins (PGs) from arachidonic acid, has been demonstrated to be induced by hypoxia and play role in angiogenesis and metastasis. To investigate the potential effect of COX-2 on hypoxia-induced VEGF expression in prostate cancer. We examined the relationship between COX-2 expression and VEGF induction in response to cobalt chloride (CoC12)-simulated hypoxia in three human prostate cancer cell lines with differing biological phenotypes. Northern blotting and ELISA revealed that all three tested cell lines constitutively expressed VEGF mRNA, and secreted VEGF protein to different degrees (LNCaP > PC-3 > PC3ML). However, these cell lines differed in the ability to produce VEGF in the presence of CoC12-simulated hypoxia. COC12 treatment resulted in 40% and 75% increases in VEGF mRNA, and 50% and 95% in protein secretion by LNCaP and PC-3 cell lines, respectively. In contrast, PC-3ML cell line, a PC-3 subline with highly invasive, metastatic phenotype, exhibits a dramatic upregulation of VEGF, 5.6-fold in mRNA and 6.3-fold in protein secretion after treatment with COC12. The upregulation of VEGF in PC-3ML cells is accompanied by a persistent induction of COX-2 mRNA (6.5- fold) and protein (5-fold). Whereas COX-2 expression is only transiently induced in PC-3 cells and not affected by COC12 in LNCaP cells. Moreover, the increases in VEGF mRNA and protein secretion induced by COC12 in PC-3ML cells were significantly suppressed following exposure to NS398, a selective COX-2 inhibitor. Finally, the effect of COX-2 inhibition on CoC12-induced VEGF production was reversed by the treatment with exogenous PGE2. Our data demonstrate that VEGF induction by cobalt chloride-simulated hypoxia is maintained by a concomitant, persistent induction of COX-2 expression and sustained elevation of PGE2 synthesis in a human metastatic prostate cancer cell line, and suggest that COX-2 activity, reflected by PGE2 production, is involved in hypoxia-induced VEGF expression, and thus, modulates prostatic tumor angiogenesis.

Original languageEnglish
Pages (from-to)687-694
Number of pages8
JournalClinical and Experimental Metastasis
Volume17
Issue number8
DOIs
StatePublished - 1999

Keywords

  • Angiogenesis
  • Cobalt chloride-simulated hypoxia
  • Cyclooxygenase-2
  • Metastasis
  • NS398
  • Prostaglandin E
  • Prostate cancer
  • Vascular endothelial growth factor

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