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

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

Research output: Contribution to journalArticle

35 Scopus citations

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. RNAi-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 RNAi-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.

Original languageEnglish (US)
Pages (from-to)1057-1067
Number of pages11
JournalCancer Biology and Therapy
Volume10
Issue number10
DOIs
StatePublished - Nov 15 2010

Keywords

  • CREB
  • Colon cancer
  • EP4 receptor
  • ERK
  • PGE
  • RNAi
  • S100P

ASJC Scopus subject areas

  • Molecular Medicine
  • Oncology
  • Pharmacology
  • Cancer Research

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