A novel angiogenic role for prostaglandin F2alpha-FP receptor interaction in human endometrial adenocarcinomas.
Prostaglandins have been implicated in several neovascular diseases. In the present study, we found elevated FP receptor and vascular endothelial growth factor (VEGF) expression colocalized in glandular epithelial and vascular cells lining the blood vessels in endometrial adenocarcinomas. We investigated the signaling pathways activated by the FP receptor and their role in modulating VEGF expression in endometrial adenocarcinoma (Ishikawa) cells. Ishikawa cells were stably transfected with FP receptor cDNA in the sense or antisense orientations. Treatment of Ishikawa cells with prostaglandin F2alpha (PGF2alpha) rapidly induced transphosphorylation of the epidermal growth factor receptor (EGFR) and phosphorylation of extracellular signal-regulated kinase (ERK) 1/2 via the FP receptor. Activation of EGFR-Ras-mitogen-activated protein kinase/ERK kinase (MEK) signaling via the FP receptor resulted in an increase in VEGF promoter activity, expression of VEGF mRNA, and secretion of VEGF protein. These effects of PGF2alpha on the FP receptor could be abolished by treatment of cells with a specific FP receptor antagonist, chemical inhibitors of c-Src, matrix metalloproteinase, and EGFR kinase or by inactivation of signaling with dominant-negative mutant isoforms of EGFR, Ras, or MEK or with small inhibitory RNA oligonucleotides targeted against the EGFR. Finally, we confirmed that PGF2alpha could potentiate angiogenesis in endometrial adenocarcinoma explants by transactivation of the EGFR and induction of VEGF mRNA expression.
Sales
Kurt J
KJ
Medical Research Council Human Reproductive Sciences Unit, Centre for Reproductive Biology, University of Edinburgh, Edinburgh, United Kingdom.
List
Tammy
T
Boddy
Sheila C
SC
Williams
Alistair R W
AR
Anderson
Richard A
RA
Naor
Zvi
Z
Jabbour
Henry N
HN
D000230:Adenocarcinoma / Q000098:blood supply* / Q000378:metabolism*; D000368:Aged; D015237:Dinoprost / Q000378:metabolism* / Q000494:pharmacology; D016889:Endometrial Neoplasms / Q000098:blood supply* / Q000378:metabolism*; D066246:ErbB Receptors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology*; D008875:Middle Aged; D009389:Neovascularization, Pathologic / Q000378:metabolism; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D011982:Receptors, Prostaglandin / Q000096:biosynthesis / Q000378:metabolism*; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism
D019408:Platelet Endothelial Cell Adhesion Molecule-1; D012333:RNA, Messenger; D011982:Receptors, Prostaglandin; D042461:Vascular Endothelial Growth Factor A; C034671:prostaglandin F2alpha receptor; D015237:Dinoprost; D066246:ErbB Receptors