title: Evidence for a pro-proliferative feedback loop in prostate cancer: the role of Epac1 and COX-2-dependent pathways.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors: Department of Pathology, Duke University Medical Center, Durham, North Carolina, United States of America.
authors: Uma Kant
authors: UK
authors: Misra
authors: Salvatore Vincent
authors: SV
authors: Pizzo
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D000242:Cyclic AMP / Q000031:analogs & derivatives / Q000494:pharmacology; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D004261:DNA Replication / Q000187:drug effects; D015232:Dinoprostone / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D008954:Models, Biological; D009287:Naphthyridines / Q000494:pharmacology; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism*; D014176:Protein Biosynthesis / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D000076223:Regulatory-Associated Protein of mTOR; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D013873:Thionucleotides / Q000494:pharmacology
chemical_list: C553294:1-(4-(4-propionylpiperazin-1-yl)-3-(trifluoromethyl)phenyl)-9-(quinolin-3-yl)benzo(h)(1,6)naphthyridin-2(1H)-one; D048868:Adaptor Proteins, Signal Transducing; D052246:Cyclooxygenase 2 Inhibitors; D020662:Guanine Nucleotide Exchange Factors; D009287:Naphthyridines; D047428:Protein Kinase Inhibitors; C116122:RAPGEF3 protein, human; C463659:RPTOR protein, human; D000076223:Regulatory-Associated Protein of mTOR; D013873:Thionucleotides; C015929:8-((4-chlorophenyl)thio)cyclic-3',5'-AMP; D000242:Cyclic AMP; D051546:Cyclooxygenase 2; D051057:Proto-Oncogene Proteins c-akt; D019893:Ribosomal Protein S6 Kinases; D058570:TOR Serine-Threonine Kinases; D015232:Dinoprostone
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