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Evidence for a pro-proliferative feedback loop in prostate cancer: the role of Epac1 and COX-2-dependent pathways.

Publication ,  Journal Article
Misra, UK; Pizzo, SV
Published in: PLoS One
2013

OBJECTIVE: In human prostate cancer cells, a selective Epac agonist, 8-CPT-2Me-cAMP, upregulates cell proliferation and survival via activation of Ras-MAPK and PI- 3-kinase-Akt-mTOR signaling cascades. Here we examine the role of inflammatory mediators in Epac1-induced cellular proliferation by determining the expression of the pro-inflammatory markers p-cPLA2, COX-2, and PGE2 in prostate cancer cells treated with 8-CPT-2Me-cAMP. METHODS: We employed inhibitors of COX-2, mTORC1, and mTORC2 to probe cyclic AMP-dependent pathways in human prostate cancer cells. RNAi targeting Epac1, Raptor, and Rictor was also employed in these studies. RESULTS: 8-CPT-2Me-cAMP treatment caused a 2-2.5-fold increase of p-cPLA2(S505), COX-2, and PGE2 levels in human prostate cancer cell lines. Pretreatment of cells with the COX-2 inhibitor SC-58125 or the EP4 antagonist AH-23848, or with an inhibitor of mTORC1 and mTORC2, Torin1, significantly reduced the Epac1-dependent increase of p-cPLA2 and COX-2, p-S6-kinase(T389), and p-AKT(S473). In addition, Epac1-induced protein and DNA synthesis were greatly reduced upon pretreatment of cells with either COX-2, EP4, or mTOR inhibitors. Transfection of prostate cancer cells with Epac1 dsRNA, Raptor dsRNA, or Rictor dsRNA profoundly reduced Epac1-dependent increases in p-cPLA2 and COX-2. CONCLUSION: We show that Epac1, a downstream effector of cAMP, functions as a pro-inflammatory modulator in prostate cancer cells and promotes cell proliferation and survival by upregulating Ras-MAPK, and PI 3-kinase-Akt-mTOR signaling.

Duke Scholars

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Published In

PLoS One

DOI

EISSN

1932-6203

Publication Date

2013

Volume

8

Issue

4

Start / End Page

e63150

Location

United States

Related Subject Headings

  • Thionucleotides
  • TOR Serine-Threonine Kinases
  • Signal Transduction
  • Ribosomal Protein S6 Kinases
  • Regulatory-Associated Protein of mTOR
  • RNA Interference
  • Proto-Oncogene Proteins c-akt
  • Protein Kinase Inhibitors
  • Protein Biosynthesis
  • Prostatic Neoplasms
 

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Misra, U. K., & Pizzo, S. V. (2013). Evidence for a pro-proliferative feedback loop in prostate cancer: the role of Epac1 and COX-2-dependent pathways. PLoS One, 8(4), e63150. https://doi.org/10.1371/journal.pone.0063150
Misra, Uma Kant, and Salvatore Vincent Pizzo. “Evidence for a pro-proliferative feedback loop in prostate cancer: the role of Epac1 and COX-2-dependent pathways.PLoS One 8, no. 4 (2013): e63150. https://doi.org/10.1371/journal.pone.0063150.
Misra, Uma Kant, and Salvatore Vincent Pizzo. “Evidence for a pro-proliferative feedback loop in prostate cancer: the role of Epac1 and COX-2-dependent pathways.PLoS One, vol. 8, no. 4, 2013, p. e63150. Pubmed, doi:10.1371/journal.pone.0063150.

Published In

PLoS One

DOI

EISSN

1932-6203

Publication Date

2013

Volume

8

Issue

4

Start / End Page

e63150

Location

United States

Related Subject Headings

  • Thionucleotides
  • TOR Serine-Threonine Kinases
  • Signal Transduction
  • Ribosomal Protein S6 Kinases
  • Regulatory-Associated Protein of mTOR
  • RNA Interference
  • Proto-Oncogene Proteins c-akt
  • Protein Kinase Inhibitors
  • Protein Biosynthesis
  • Prostatic Neoplasms