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

Anupama Chandramouli, Melania Mercado-Pimentel, Anthony Hutchinson, Adriana Gibadulinová, Erik R. Olson, Sally E 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

29 Citations (Scopus)

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

Fingerprint

Receptors, Prostaglandin E, EP4 Subtype
Dinoprostone
Colonic Neoplasms
RNA Interference
Sequence Deletion
Messenger RNA
Cell Movement
Growth
EF Hand Motifs
Calcium-Binding Proteins
MAP Kinase Signaling System
Luciferases
Pancreatic Neoplasms
Colorectal Neoplasms
Neoplasms
Colon
Pharmacology
Breast Neoplasms

Keywords

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

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Molecular Medicine
  • Pharmacology

Cite this

The induction of S100p expression by the prostaglandin E2 (PGE2)/EP4 receptor signaling pathway in colon cancer cells. / Chandramouli, Anupama; Mercado-Pimentel, Melania; Hutchinson, Anthony; Gibadulinová, Adriana; Olson, Erik R.; Dickinson, Sally E; Shañas, Reneé; Davenport, Jennifer; Owens, Janae; Bhattacharyya, Achyut K; Regan, John W; Pastorekova, Silvia; Arumugam, Thiruvengadam; Logsdon, Craig D.; Nelson, Mark A.

In: Cancer Biology and Therapy, Vol. 10, No. 10, 15.11.2010, p. 1057-1067.

Research output: Contribution to journalArticle

Chandramouli, A, Mercado-Pimentel, M, Hutchinson, A, Gibadulinová, A, Olson, ER, Dickinson, SE, Shañas, R, Davenport, J, Owens, J, Bhattacharyya, AK, Regan, JW, Pastorekova, S, Arumugam, T, Logsdon, CD & Nelson, MA 2010, 'The induction of S100p expression by the prostaglandin E2 (PGE2)/EP4 receptor signaling pathway in colon cancer cells', Cancer Biology and Therapy, vol. 10, no. 10, pp. 1057-1067. https://doi.org/10.4161/cbt.10.10.13373
Chandramouli, Anupama ; Mercado-Pimentel, Melania ; Hutchinson, Anthony ; Gibadulinová, Adriana ; Olson, Erik R. ; Dickinson, Sally E ; Shañas, Reneé ; Davenport, Jennifer ; Owens, Janae ; Bhattacharyya, Achyut K ; Regan, John W ; Pastorekova, Silvia ; Arumugam, Thiruvengadam ; Logsdon, Craig D. ; Nelson, Mark A. / The induction of S100p expression by the prostaglandin E2 (PGE2)/EP4 receptor signaling pathway in colon cancer cells. In: Cancer Biology and Therapy. 2010 ; Vol. 10, No. 10. pp. 1057-1067.
@article{63ae0de5514b45aeacb03530dad0bafa,
title = "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. 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.",
keywords = "Colon cancer, CREB, EP4 receptor, ERK, PGE, RNAi, S100P",
author = "Anupama Chandramouli and Melania Mercado-Pimentel and Anthony Hutchinson and Adriana Gibadulinov{\'a} and Olson, {Erik R.} and Dickinson, {Sally E} and Rene{\'e} Sha{\~n}as and Jennifer Davenport and Janae Owens and Bhattacharyya, {Achyut K} and Regan, {John W} and Silvia Pastorekova and Thiruvengadam Arumugam and Logsdon, {Craig D.} and Nelson, {Mark A}",
year = "2010",
month = "11",
day = "15",
doi = "10.4161/cbt.10.10.13373",
language = "English (US)",
volume = "10",
pages = "1057--1067",
journal = "Cancer Biology and Therapy",
issn = "1538-4047",
publisher = "Landes Bioscience",
number = "10",

}

TY - JOUR

T1 - The induction of S100p expression by the prostaglandin E2 (PGE2)/EP4 receptor signaling pathway in colon cancer cells

AU - Chandramouli, Anupama

AU - Mercado-Pimentel, Melania

AU - Hutchinson, Anthony

AU - Gibadulinová, Adriana

AU - Olson, Erik R.

AU - Dickinson, Sally E

AU - Shañas, Reneé

AU - Davenport, Jennifer

AU - Owens, Janae

AU - Bhattacharyya, Achyut K

AU - Regan, John W

AU - Pastorekova, Silvia

AU - Arumugam, Thiruvengadam

AU - Logsdon, Craig D.

AU - Nelson, Mark A

PY - 2010/11/15

Y1 - 2010/11/15

N2 - 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.

AB - 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.

KW - Colon cancer

KW - CREB

KW - EP4 receptor

KW - ERK

KW - PGE

KW - RNAi

KW - S100P

UR - http://www.scopus.com/inward/record.url?scp=78549254601&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=78549254601&partnerID=8YFLogxK

U2 - 10.4161/cbt.10.10.13373

DO - 10.4161/cbt.10.10.13373

M3 - Article

C2 - 20890108

AN - SCOPUS:78549254601

VL - 10

SP - 1057

EP - 1067

JO - Cancer Biology and Therapy

JF - Cancer Biology and Therapy

SN - 1538-4047

IS - 10

ER -