Upregulation of VEGF by 15-deoxy-Delta12,14-prostaglandin J2 via heme oxygenase-1 and ERK1/2 signaling in MCF-7 cells.

Abstract

The vascular endothelial growth factor (VEGF) induces angiogenesis in ischemic or inflamed tissues during tumor growth. 15-Deoxy-Delta12,14-prostaglandin J2 (15d-PGJ2), an endogenous ligand of peroxisome proliferator-activated receptor (PPAR) gamma, has been reported to upregulate VEGF synthesis through the induction of heme oxygenase (HO)-1. In this work, we found that treatment of human breast cancer (MCF-7) cells with 15d-PGJ2 led to time-dependent increases in the expression of HO-1. The PPAR gamma antagonist GW9662 and N-acetylcysteine failed to block induction of HO-1 by 15d-PGJ2. Elevated expression or activity of HO-1 has been reported to stimulate proliferation and to accelerate angiogenesis in several tumor cells. The induction of HO-1 expression preceded the upregulation of VEGF in MCF-7 cells stimulated with 15d-PGJ2. In another experiment, 15d-PGJ2 induced phosphorylation of extracellular signal-regulated kinase (ERK1/2) in 12 h. Treatment of MCF-7 cells with U0126 or transient transfection with dominant negative ERK (DN-ERK) abrogated 15d-PGJ2-induced VEGF expression. To determine whether the induction of HO-1 is responsible for ERK1/2 activation, the HO-1 inhibitor, zinc protoporphyrin (ZnPP) was used. The phosphorylation of ERK1/2 by 15d-PGJ2 was abolished by ZnPP. These results suggest that 15d-PGJ2 upregulates VEGF expression via induction of HO-1 and ERK-1 and -2 phosphorylation, which may contribute to increased angiogenesis of the tumor cells.

• Authors: Eun-Hee Kim, Hye-Kyung Na, Young-Joon Surh
• Journal: Annals of the New York Academy of Sciences (Ann N Y Acad Sci) Vol. 1090 Pg. 375-84 (Dec 2006) ISSN: 0077-8923 [Print] United States
• PMID: 17384282 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 15-deoxy-delta(12,14)-prostaglandin J2
• DNA Primers
• Vascular Endothelial Growth Factor A
• Heme Oxygenase (Decyclizing)
• Mitogen-Activated Protein Kinase 1
• Mitogen-Activated Protein Kinase 3
• Prostaglandin D2

Topics

• Base Sequence
• Cell Line, Tumor
• DNA Primers
• Heme Oxygenase (Decyclizing) (metabolism)
• Humans
• Mitogen-Activated Protein Kinase 1 (metabolism)
• Mitogen-Activated Protein Kinase 3 (metabolism)
• Prostaglandin D2 (analogs & derivatives, pharmacology)
• Reverse Transcriptase Polymerase Chain Reaction
• Signal Transduction
• Up-Regulation
• Vascular Endothelial Growth Factor A (metabolism)