20890108

pubmed:Citation

10

BACKGROUND: Prostaglandin E? (PGE?) levels are frequently elevated in colorectal carcinomas. PGE? is perceived via four transmembrane G protein coupled receptors (EP1-4), among which the EP4 receptor is most relevant. PGE?/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 PGE? 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 PGE?-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 PGE?-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 PGE?/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 PGE?/EP4 receptor signaling may have important consequences relevant to colon cancer pathogenesis.

eng

IM

MEDLINE

1555-8576

Electronic

NLM

1056-66

pubmed-meshheading:20890108-Blotting, Western, pubmed-meshheading:20890108-Calcium-Binding Proteins, pubmed-meshheading:20890108-Colonic Neoplasms, pubmed-meshheading:20890108-Colony-Forming Units Assay, pubmed-meshheading:20890108-Cyclic AMP Response Element-Binding Protein, pubmed-meshheading:20890108-Dinoprostone, pubmed-meshheading:20890108-Electrophoretic Mobility Shift Assay, pubmed-meshheading:20890108-Extracellular Signal-Regulated MAP Kinases, pubmed-meshheading:20890108-Humans, pubmed-meshheading:20890108-Mitogen-Activated Protein Kinase Kinases, pubmed-meshheading:20890108-Mutagenesis, Site-Directed, pubmed-meshheading:20890108-Mutation, pubmed-meshheading:20890108-Neoplasm Proteins, pubmed-meshheading:20890108-RNA, Messenger, pubmed-meshheading:20890108-RNA, Small Interfering, pubmed-meshheading:20890108-Receptors, Prostaglandin E, EP4 Subtype, pubmed-meshheading:20890108-Reverse Transcriptase Polymerase Chain Reaction, pubmed-meshheading:20890108-Signal Transduction, pubmed-meshheading:20890108-Tumor Cells, Cultured

The induction of S100p expression by the Prostaglandin E? (PGE?)/EP4 receptor signaling pathway in colon cancer cells.

Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural