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.