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
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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.
Cancer biology & therapy 11/2010; 10(10):1056-66. · 2.64 Impact Factor
