Upregulation of VEGF by 15-deoxy-Delta12,14-prostaglandin J2 via heme oxygenase-1 and ERK1/2 signaling in MCF-7 cells.
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.
Kim
Eun-Hee
EH
Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Shinlim-dong, Kwanak-ku, Seoul 151-742, Korea.
Na
Hye-Kyung
HK
Surh
Young-Joon
YJ
D001483:Base Sequence; D045744:Cell Line, Tumor; D017931:DNA Primers; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism*; D006801:Humans; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
C097240:15-deoxy-delta(12,14)-prostaglandin J2; D017931:DNA Primers; D042461:Vascular Endothelial Growth Factor A; D006419:Heme Oxygenase (Decyclizing); D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D015230:Prostaglandin D2