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 12,14-Prostaglandin J2 via Heme Oxygenase-1 and ERK1/2 Signaling in MCF-7 Cells
a Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 151-742, Korea
Key Words: 15-deoxy-  12, 14-prostaglandin J2 • heme oxygenase-1 • VEGF • ERK • MCF-7 cells
Address for correspondence: Prof. Young-Joon Surh, College of Pharmacy, Seoul National University, Shinlim-dong, Kwanak-ku, Seoul 151-742, Korea. Voice: +82-2-880-7845; fax: +82-2-874-9775. e-mail: surh{at}plaza.snu.ac.kr
The vascular endothelial growth factor (VEGF) induces angiogenesis in ischemic or inflamed tissues during tumor growth. 15-Deoxy-
12,14-prostaglandin J2 (15d-PGJ2), an endogenous ligand of peroxisome proliferator-activated receptor (PPAR)  , 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 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.
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