title: cAMP signalling protects proximal tubular epithelial cells from cisplatin-induced apoptosis via activation of Epac.
abstract: OBJECTIVE
  Nephrotoxicity is the principal dose-limiting factor for cisplatin chemotherapy and is primarily associated with proximal tubular epithelial cells, including disruption of cell adhesions and induction of apoptosis. Cell adhesion and survival is regulated by, amongst other factors, the small GTPase Rap and its activator, the exchange protein directly activated by cAMP (Epac). Epac is particularly enriched in renal tubule epithelium. This study investigates the cytoprotective effects of cAMP-Epac-Rap signalling in a model of cisplatin-induced renal cell injury.
  
  
  METHODS
  The Epac-selective cAMP analogue 8-pCPT-2'-O-Me-cAMP was used to activate the Epac-Rap signalling pathway in proximal tubular epithelial cells. Cells were exposed to cisplatin, in the presence or absence of 8-pCPT-2'-O-Me-cAMP, and nephrotoxicity was determined by monitoring cell-cell junctions and cell apoptosis.
  
  
  RESULTS
  Activation of Epac-Rap signalling preserves cell-cell junctions and protects against cell apoptosis of mouse proximal tubular cells during cisplatin treatment. Activation with the Epac-selective cAMP analogue 8-pCPT-2'-O-Me-cAMP or receptor-mediated induction of cAMP both induced cytoprotection against cisplatin, whereas a PKA-selective cAMP analogue was not cytoprotective. 8-pCPT-2'-O-Me-cAMP mediated cytoprotection was blocked by RNAi-mediated silencing of Epac-Rap signalling in these cells. In contrast, 8-pCPT-2'-O-Me-cAMP did not protect against cisplatin-induced cell death of cancer cells that lacked Epac1 expression.
  
  
  CONCLUSIONS
  Our study identifies activation of Epac-Rap signalling as a potential strategy for reducing the nephrotoxicity associated with cisplatin treatments and, as a result, broadens the therapeutic window of this chemotherapeutic agent.
authors: Division of Toxicology, Leiden/Amsterdam Center for Drug Research, Leiden University, Leiden, the Netherlands.
authors: Yu
authors: Y
authors: Qin
authors: Geurt
authors: G
authors: Stokman
authors: Kuan
authors: K
authors: Yan
authors: Sreenivasa
authors: S
authors: Ramaiahgari
authors: Fons
authors: F
authors: Verbeek
authors: Marjo
authors: M
authors: de Graauw
authors: Bob
authors: B
authors: van de Water
authors: Leo S
authors: LS
authors: Price
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D000242:Cyclic AMP / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology; D004847:Epithelial Cells / Q000378:metabolism; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D010750:Phosphoproteins / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction; D062826:Zonula Occludens-1 Protein; D051176:beta Catenin / Q000378:metabolism; D020827:rap1 GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: C473217:8-(4-chloro-phenylthio)-2'-O-methyladenosine-3'-5'-cyclic monophosphate; D000970:Antineoplastic Agents; C482601:Epac protein, mouse; D020662:Guanine Nucleotide Exchange Factors; D008565:Membrane Proteins; D010750:Phosphoproteins; C116122:RAPGEF3 protein, human; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C569042:TJP1 protein, human; C569043:Tjp1 protein, mouse; D062826:Zonula Occludens-1 Protein; D051176:beta Catenin; D000242:Cyclic AMP; D053148:Caspase 3; D020827:rap1 GTP-Binding Proteins; D002945:Cisplatin