cAMP signalling protects proximal tubular epithelial cells from cisplatin-induced apoptosis via activation of Epac
| Autor: | Yu, Qin, Geurt, Stokman, Kuan, Yan, Sreenivasa, Ramaiahgari, Fons, Verbeek, Marjo, de Graauw, Bob, van de Water, Leo S, Price |
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| Rok vydání: | 2011 |
| Předmět: |
Male
Caspase 3 Membrane Proteins rap1 GTP-Binding Proteins Antineoplastic Agents Apoptosis Epithelial Cells Phosphoproteins Research Papers Cell Line Kidney Tubules Proximal Mice Inbred C57BL Mice Cell Line Tumor Cyclic AMP Zonula Occludens-1 Protein Animals Guanine Nucleotide Exchange Factors Humans RNA Messenger Cisplatin RNA Small Interfering beta Catenin Signal Transduction |
| Zdroj: | British journal of pharmacology. 165(4b) |
| ISSN: | 1476-5381 |
| Popis: | 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.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.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.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. |
| Databáze: | OpenAIRE |
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