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 254bp (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.
Written by:
Peng Y, Shi J, Du X, Wang L, Klocker H, Mo L, Mo Z, Zhang J. Are you the author?
College of Life Sciences and State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin 300071, China
Reference: Int J Biochem Cell Biol. 2013 Mar;45(3):521-30
doi: 10.1016/j.biocel.2012.11.017
PubMed Abstract
PMID: 23246486
