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Title: The induction of S100p expression by the Prostaglandin E₂ (PGE₂)/EP4 receptor signaling pathway in colon cancer cells.

Authors: Chandramouli, Anupama; Mercado-Pimentel, Melania E; Hutchinson, Anthony; Gibadulinová, Adriana; Olson, Erik R; Dickinson, Sally; Shañas, Reneé; Davenport, Jennifer; Owens, Janae; Bhattacharyya, Achyut K; Regan, John W; Pastorekova, Silvia; Arumugam, Thiruvengadam; Logsdon, Craig D; Nelson, Mark A

Published In Cancer Biol Ther, (2010 Nov 15)

Abstract: BACKGROUND: Prostaglandin E₂ (PGE₂) levels are frequently elevated in colorectal carcinomas. PGE₂ is perceived via four transmembrane G protein coupled receptors (EP1-4), among which the EP4 receptor is most relevant. PGE₂/EP4-receptor interaction activates CREB via the ERK/MEK pathway. However, the downstream target genes activated by this pathway remained to be investigated. METHODOLOGY/PRINICIPAL FINDINGS: Here, we have identified S100P (an EF-hand calcium binding protein) as a novel downstream target. We show by realtime RT-PCR that S100P mRNA levels are elevated in 14/17 (82%) colon tumor tissues as compared to paired adjacent normal colonic tissues. S100P expression is stimulated in the presence of PGE₂ in a time dependent manner at mRNA and protein levels in colon, breast and pancreatic cancer cells. Pharmacological and RNAi-mediated inhibition of the EP4 receptor attenuates PGE₂-dependent S100P mRNA induction. RNA(i)-mediated knockdown of CREB inhibits endogenous S100P expression. Furthermore, using luciferase reporter analysis and EMSA we show that mutation and/or deletion of the CRE sequence within the S100P promoter abolished PGE₂-mediated transcriptional induction. Finally, we demonstrate that RNA(i)-mediated knockdown of S100P compromised invadopodia formation, colony growth and motility of colon cancer cells. Interestingly, endogenous knock down of S100P decreases ERK expression levels, suggesting a role for ERK in regulating S100P mediated cell growth and motility. CONCLUSIONS/SIGNIFICANCE: Together, our findings show for the first time that S100P expression is regulated by PGE₂/EP4-receptor signaling and may participate in a feedback signaling that perpetuates tumor cell growth and migration. Therefore, our data suggest that dysregulated S100P expression resulting from aberrant PGE₂/EP4 receptor signaling may have important consequences relevant to colon cancer pathogenesis.

PubMed ID: 20890108 Exiting the NIEHS site

MeSH Terms: Blotting, Western; Calcium-Binding Proteins/antagonists & inhibitors; Calcium-Binding Proteins/genetics; Calcium-Binding Proteins/metabolism*; Colonic Neoplasms/genetics; Colonic Neoplasms/metabolism*; Colonic Neoplasms/pathology; Colony-Forming Units Assay; Cyclic AMP Response Element-Binding Protein/genetics; Cyclic AMP Response Element-Binding Protein/metabolism; Dinoprostone/genetics; Dinoprostone/metabolism*; Electrophoretic Mobility Shift Assay; Extracellular Signal-Regulated MAP Kinases/genetics; Extracellular Signal-Regulated MAP Kinases/metabolism; Humans; Mitogen-Activated Protein Kinase Kinases/genetics; Mitogen-Activated Protein Kinase Kinases/metabolism; Mutagenesis, Site-Directed; Mutation/genetics; Neoplasm Proteins/antagonists & inhibitors; Neoplasm Proteins/genetics; Neoplasm Proteins/metabolism*; RNA, Messenger/genetics; RNA, Small Interfering/genetics; Receptors, Prostaglandin E, EP4 Subtype/genetics; Receptors, Prostaglandin E, EP4 Subtype/metabolism*; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction*; Tumor Cells, Cultured

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