Expression, Localization, and Signaling of Prostaglandin F_2αReceptor in Human Endometrial Adenocarcinoma: Regulation of Proliferation by Activation of the Epidermal Growth Factor Receptor and Mitogen-Activated Protein Kinase Signaling Pathways

Abstract

Prostaglandin F(2 alpha)(PGF(2 alpha)) is a bioactive lipid biosynthesized by cyclooxygenase (COX) enzymes and mediates its biological activity via the heptahelical G(q)-coupled PGF(2 alpha)receptor (FP receptor). This study investigated the expression and molecular signaling of the FP receptor in human endometrial adenocarcinomas. Real-time RT-PCR and Western blot analysis confirmed FP receptor expression in endometrial adenocarcinoma of all grades and differentiation. The expression of FP receptor was up-regulated in all endometrial adenocarcinomas compared with normal endometrium. The site of FP receptor expression was localized by in situ hybridization and immunohistochemistry to the neoplastic epithelial cells in all adenocarcinomas. Treatment of endometrial adenocarcinoma explants with PGF(2 alpha) resulted in mobilization of inositol phosphate signaling, indicating functional FP receptor expression. We investigated whether PGF(2 alpha) could trans-activate the epidermal growth factor receptor (EGFR) and trigger the MAPK signaling pathway. Treatment of adenocarcinoma explants and endometrial adenocarcinoma cells (Ishikawa) with PGF(2 alpha)-phosphorylated EGFR, triggered MAPK signaling and enhanced the proliferation of Ishikawa cells. Inactivation of phospholipase C, EGFR kinase, and MAPK kinase with specific inhibitors abolished PGF(2 alpha)-induced trans-activation of EGFR, MAPK signaling, and Ishikawa cell proliferation. These data suggest that PGF(2 alpha)-FP receptor promote endometrial tumorigenesis via a phospholipase C-mediated phosphorylation of the EGFR and MAPK signaling pathways.

Autocrine production of prostaglandin F2α enhances phenotypic transformation of normal rat kidney fibroblasts

“…The growth-stimulatory action of PGF 2␣ requires binding to its FP receptor, whereas activation of this receptor is also involved in the autocrine enhancement of RA-induced transformation by PGF 2␣ . On the basis of these results, the FP receptor seems to be a potential target in medical therapies, particularly because elevated expression of functional FP receptors has been reported in human endometrial adenocarcinomas (26).…”

An indomethacin analogue, N-(4-chlorobenzoyl)-melatonin, is a selective inhibitor of aldo-keto reductase 1C3 (type 2 3α-HSD, type 5 17β-HSD, and prostaglandin F synthase), a potential target for the treatment of hormone dependent and hormone independent malignancies

“…In addition, the prostaglandin F synthase activity of AKR1C3 will alter signaling pathways and stimulate the proliferation of both hormone-dependent and hormoneindependent cancers. The PGF 2 isomers will stimulate the Gq-coupled F prostanoid receptor and activate signal cascades associated with proliferation and the inhibition of differentiation [11][12][13]. Reduction of PGD 2 levels by AKR1C3 will prevent its dehydration and rearrangement to form the J-series prostaglandins.…”

“…Of its endogenously relevant substrates, AKR1C3 has the highest catalytic activity for the reduction of PGD 2 [9;10]. The PGF 2 isomers will activate the Gq-coupled F-prostanoid receptor and initiate protein kinase C and MAPK signaling cascades that stimulate proliferation through mechanisms that include inhibition of the peroxisome proliferator-activated receptor γ (PPARγ) and activation of NF-κB [11][12][13][14]. The AKR1C3-mediated depletion of PGD 2 will also prevent the formation of anti-proliferative PGJ 2 isomers, including 15-deoxy-Δ12,14-PGJ 2 , which are natural PPARγ ligands and inhibitors of NF-κB signaling [15][16][17][18].…”

The Aldo-Keto Reductase Superfamily and its Role in Drug Metabolism and Detoxification

“…Likewise, in the breast, AKR1C3 helps create pro-estrogenic state by enhancing the synthesis of 17β-estradiol and inactivating progesterone (Byrns et al, 2008); 2) by converting PGD 2 to 9α,11β-PGF 2 , AKR1C3 diverts the metabolism of the former from forming 15-deoxy-Δ 12,14 -PGJ 2 , thus depriving PPARγ receptor of its ligand and preventing terminal differentiation of myeloid leukemia cells (Desmond et al, 2003). PGF 2 and its isomers stimulate proliferation through F-prostanoid receptor (Chen et al, 1998;Sales et al, 2004); 3) AKR1C3 is overexpressed in several types of cancer (Stanbrough et al, 2006;Li et al, 2004).…”