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Upregulation of VEGF by 15‐Deoxy‐Δ 12,14 ‐Prostaglandin J 2 via Heme Oxygenase‐1 and ERK1/2 Signaling in MCF‐7 Cells
Author(s) -
KIM EUNHEE,
NA HYEKYUNG,
SURH YOUNGJOON
Publication year - 2006
Publication title -
annals of the new york academy of sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.712
H-Index - 248
eISSN - 1749-6632
pISSN - 0077-8923
DOI - 10.1196/annals.1378.041
Subject(s) - heme oxygenase , mapk/erk pathway , angiogenesis , downregulation and upregulation , vascular endothelial growth factor , phosphorylation , kinase , zinc protoporphyrin , chemistry , cancer research , vascular endothelial growth factor a , microbiology and biotechnology , biology , heme , biochemistry , vegf receptors , gene , enzyme
The vascular endothelial growth factor (VEGF) induces angiogenesis in ischemic or inflamed tissues during tumor growth. 15‐Deoxy‐Δ 12,14 ‐prostaglandin J 2 (15d‐PGJ 2 ), an endogenous ligand of peroxisome proliferator‐activated receptor (PPAR) γ, 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‐PGJ 2 led to time‐dependent increases in the expression of HO‐1. The PPAR γ antagonist GW9662 and N ‐acetylcysteine failed to block induction of HO‐1 by 15d‐PGJ 2 . 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‐PGJ 2 . In another experiment, 15d‐PGJ 2 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‐PGJ 2 ‐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‐PGJ 2 was abolished by ZnPP. These results suggest that 15d‐PGJ 2 upregulates VEGF expression via induction of HO‐1 and ERK‐1 and ‐2 phosphorylation, which may contribute to increased angiogenesis of the tumor cells.