title: Prostaglandin E2 induces stromal cell-derived factor-1 expression in prostate stromal cells by activating protein kinase A and transcription factor Sp1.
abstract: Recent reports indicate prostaglandin E2 (PGE2) can modulate tumor environment and promote angiogenesis through induction of stromal cell-derived factor 1 (SDF-1) production. We investigated the mechanism of PGE2-induced SDF-1 regulation in human prostate stromal cell and analyzed the effects in a stromal-epithelial interaction model. PGE2 stimulation increased SDF-1 expression in the prostate stromal cell lines WPMY-1 and NAF. We revealed signaling through the PGE2 receptor EP3 and activation of protein kinase A (PKA) are required. The EP3 agonist sulprostone and the cAMP analog forskolin mimicked and the EP3 siRNA, antagonist L798106 and the PKA inhibitor H89 abrogated the effect of PGE2 on SDF-1 expression. SDF-1 promoter truncation experiments demonstrated a 254 bp (from nt -219 to nt +34) SDF-1 proximal promoter fragment containing 5 putative transcription factor Sp1 binding motifs is sufficient for PGE2 induction. CHIP assays confirmed binding and PGE2 induced recruitment of Sp1 to the SDF-1 promoter. Sp1 motif mutation identified Sp1 motifs -140/-133 and -9/+1 as the crucial elements responsible for PGE2 induction. Moreover, SDF-1 was up- or down-regulated by Sp1 over-expression or knock-down. We also demonstrate stimulation of migration of prostate cancer cell lines PC3 and DU145 with conditioned media collected from WPMY-1 or NAF cells stimulated with PGE2 and blockade of enhanced migration by a SDF-1 neutralizing antibody. In conclusion, we provide evidence for a paracrine prostate stromal-epithelial interaction induced by upregulation of expression of SDF-1 by PGE2. Our research provides new insights into the mechanism promoting metastasis of prostate carcinoma via stromal-epithelial interaction.
authors.affiliation: College of Life Sciences and State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin 300071, China.
authors.forename: Yanfei
authors.initials: Y
authors.lastname: Peng
authors.forename: Jiandang
authors.initials: J
authors.lastname: Shi
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Du
authors.forename: Liang
authors.initials: L
authors.lastname: Wang
authors.forename: Helmut
authors.initials: H
authors.lastname: Klocker
authors.forename: Linjian
authors.initials: L
authors.lastname: Mo
authors.forename: Zengnan
authors.initials: Z
authors.lastname: Mo
authors.forename: Ju
authors.initials: J
authors.lastname: Zhang
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement; D054377:Chemokine CXCL12 / Q000235:genetics* / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics* / Q000378:metabolism; D015232:Dinoprostone / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism; D006801:Humans; D008297:Male; D009362:Neoplasm Metastasis; D011401:Promoter Regions, Genetic; D011467:Prostate / Q000378:metabolism / Q000473:pathology; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D018078:Receptors, Prostaglandin E / Q000378:metabolism; D058308:Receptors, Prostaglandin E, EP3 Subtype; D015398:Signal Transduction / Q000187:drug effects; D016329:Sp1 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D017154:Stromal Cells / Q000378:metabolism / Q000473:pathology; D015533:Transcriptional Activation; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D054377:Chemokine CXCL12; C545647:PTGER3 protein, human; D018078:Receptors, Prostaglandin E; D058308:Receptors, Prostaglandin E, EP3 Subtype; D016329:Sp1 Transcription Factor; D017868:Cyclic AMP-Dependent Protein Kinases; D015232:Dinoprostone