Unknown

Dataset Information

0

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


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.

SUBMITTER: Chandramouli A 

PROVIDER: S-EPMC3047097 | biostudies-literature |

REPOSITORIES: biostudies-literature

Similar Datasets

| S-EPMC8660993 | biostudies-literature
| S-EPMC4582666 | biostudies-literature
| S-EPMC6427013 | biostudies-literature
| S-EPMC3081002 | biostudies-literature
| S-EPMC3996215 | biostudies-literature
| S-EPMC4741781 | biostudies-literature
| S-EPMC4786633 | biostudies-literature
| S-EPMC6478873 | biostudies-literature
| S-EPMC10557697 | biostudies-literature
| S-EPMC3726211 | biostudies-literature