PMID- 23103562
OWN - NLM
STAT- MEDLINE
DCOM- 20130225
LR  - 20131121
IS  - 1873-2968 (Electronic)
IS  - 0006-2952 (Linking)
VI  - 85
IP  - 2
DP  - 2013 Jan 15
TI  - TNF-alpha-mediated NF-kappaB survival signaling impairment by cisplatin enhances JNK 
      activation allowing synergistic apoptosis of renal proximal tubular cells.
PG  - 274-86
LID - S0006-2952(12)00688-0 [pii]
LID - 10.1016/j.bcp.2012.10.012 [doi]
AB  - Cisplatin-induced nephrotoxicity is an important limiting factor for cisplatin 
      use. Tumor necrosis factor-alpha (TNF-alpha) is known to contribute to cisplatin-induced 
      nephrotoxicity by inducing an inflammatory process aggravating the primary 
      injury, thereby resulting in acute kidney injury (AKI). The present study 
      investigates the pathways synergistically activated by cisplatin and TNF-alpha 
      responsible for TNF-alpha-enhanced cisplatin-induced renal cell injury. To do so, 
      immortalized renal proximal tubular epithelial cells (IM-PTECs) were co-treated 
      with TNF-alpha and cisplatin. Under these conditions, cisplatin induced 
      dose-dependent apoptosis in IM-PTECs, which was significantly enhanced by TNF-alpha. 
      Transcriptomic analysis revealed that cisplatin inhibited the typical TNF-alpha 
      response and cisplatin/TNF-alpha treatment up-regulated cell death pathways while it 
      down-regulated survival pathways compared to cisplatin alone. In concordance, the 
      gene expression levels of kidney injury markers combined with activation of 
      specific inflammatory mediators were enhanced by cisplatin/TNF-alpha treatment, 
      resembling the in vivo cisplatin-induced nephrotoxicity response. Furthermore, 
      combined cisplatin/TNF-alpha treatment inhibited NF-kappaB nuclear translocation and 
      NF-kappaB-mediated gene transcription leading to enhanced and prolonged JNK and c-Jun 
      phosphorylation. JNK sustained activation further inhibited NF-kappaB signaling via a 
      feedback loop mechanism. This led to an alteration in the transcription of the 
      NF-kappaB-induced anti-apoptotic genes c-IAP2, Bcl-XL, Bruce and Bcl2 and 
      pro-apoptotic genes Bfk and Xaf1 and consequently to sensitization of the 
      IM-PTECs toward cisplatin/TNF-alpha-induced toxicity. In conclusion, our findings 
      support a model whereby renal cells exposed to both cisplatin and TNF-alpha switch 
      into a more pro-apoptotic and inflammatory program by altering their 
      NF-kappaB/JNK/c-Jun balance.
CI  - Copyright (c) 2012 Elsevier Inc. All rights reserved.
FAU - Benedetti, Giulia
AU  - Benedetti G
AD  - Division of Toxicology, Leiden/Amsterdam Center for Drug Research, Leiden 
      University, The Netherlands.
FAU - Fredriksson, Lisa
AU  - Fredriksson L
FAU - Herpers, Bram
AU  - Herpers B
FAU - Meerman, John
AU  - Meerman J
FAU - van de Water, Bob
AU  - van de Water B
FAU - de Graauw, Marjo
AU  - de Graauw M
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20121024
PL  - England
TA  - Biochem Pharmacol
JT  - Biochemical pharmacology
JID - 0101032
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Apoptosis Regulatory Proteins)
RN  - 0 (NF-kappa B)
RN  - 0 (RNA, Small Interfering)
RN  - 0 (Recombinant Proteins)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - Q20Q21Q62J (Cisplatin)
SB  - IM
MH  - Animals
MH  - Antineoplastic Agents/adverse effects/*pharmacology
MH  - Apoptosis/*drug effects
MH  - Apoptosis Regulatory Proteins/genetics/metabolism
MH  - Cell Line, Transformed
MH  - Cisplatin/adverse effects/*pharmacology
MH  - Drug Resistance
MH  - Gene Expression Regulation/drug effects
MH  - Genes, Reporter/drug effects
MH  - Kidney Tubules, Proximal/cytology/*drug effects/immunology/metabolism
MH  - MAP Kinase Signaling System/*drug effects
MH  - Mice
MH  - NF-kappa B/genetics/*metabolism
MH  - Phosphorylation/drug effects
MH  - Protein Processing, Post-Translational/drug effects
MH  - RNA Interference
MH  - RNA, Small Interfering
MH  - Recombinant Proteins/antagonists & inhibitors/metabolism
MH  - Transcription, Genetic/drug effects
MH  - Tumor Necrosis Factor-alpha/genetics/*metabolism
EDAT- 2012/10/30 06:00
MHDA- 2013/02/26 06:00
CRDT- 2012/10/30 06:00
PHST- 2012/09/22 00:00 [received]
PHST- 2012/10/16 00:00 [revised]
PHST- 2012/10/17 00:00 [accepted]
PHST- 2012/10/30 06:00 [entrez]
PHST- 2012/10/30 06:00 [pubmed]
PHST- 2013/02/26 06:00 [medline]
AID - S0006-2952(12)00688-0 [pii]
AID - 10.1016/j.bcp.2012.10.012 [doi]
PST - ppublish
SO  - Biochem Pharmacol. 2013 Jan 15;85(2):274-86. doi: 10.1016/j.bcp.2012.10.012. Epub 
      2012 Oct 24.