Restoration of CREB function ameliorates cisplatin cytotoxicity in renal tubular cells.
We have shown that mouse proximal tubule cells (TKPTS) survive H(2)O(2) stress by activating the cAMP-responsive element binding protein (CREB)-mediated transcription via the canonical EGFR-Ras/ERK pathway. By contrast, cisplatin activates EGFR/Ras/ERK signaling in TKPTS cells yet promotes cell death rather than survival. We now demonstrate that the cisplatin-induced activated EGFR/Ras/ERK signaling cascade fails to activate CREB-mediated transcription even in the presence of phosphorylated CREB. CREB-mediated transcription as well as survival was restored by the histone deacetylase (HDAC) inhibitor trichostatine A (TSA), an effective chemotherapeutic agent. Similar to severe oxidant stress, TSA-mediated survival could be abrogated by inhibition of CREB-mediated transcription. These studies confirm the importance of CREB-mediated transcription in the survival of renal cells subjected to either oxidant- or cisplatin-induced stress. The use of cisplatin and TSA in combined chemotherapy protocols may be an effective strategy to enhance cancer cell death and limit nephrotoxicity.
Arany
Istvan
I
Department of Internal Medicine, University of Arkansas for Medical Sciences and Central Arkansas Veterans Healthcare System, Little Rock, Arkansas, USA. iarany@ped.umsmed.edu
Herbert
Johann
J
Herbert
Zsolt
Z
Safirstein
Robert L
RL
D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D002945:Cisplatin / Q000633:toxicity*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids / Q000494:pharmacology; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D010766:Phosphorylation; D013312:Stress, Physiological / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects
D000970:Antineoplastic Agents; D017362:Cyclic AMP Response Element-Binding Protein; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; C012589:trichostatin A; D048049:Extracellular Signal-Regulated MAP Kinases; D002945:Cisplatin