PMID- 29033791
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20210924
IS  - 1662-5102 (Print)
IS  - 1662-5102 (Electronic)
IS  - 1662-5102 (Linking)
VI  - 11
DP  - 2017
TI  - Protein Synthesis Inhibition and Activation of the c-Jun N-Terminal Kinase Are 
      Potential Contributors to Cisplatin Ototoxicity.
PG  - 303
LID - 10.3389/fncel.2017.00303 [doi]
LID - 303
AB  - Cisplatin has been regarded as an effective and versatile chemotherapeutic agent 
      for nearly 40 years. Though the associated dose-dependent ototoxicity is known, 
      the cellular mechanisms by which cochleovestibular hair cell death occur are not 
      well understood. We have previously shown that aminoglycoside ototoxicity is 
      mediated in part by cytosolic protein synthesis inhibition. Despite a lack of 
      molecular similarity, aminoglycosides were shown to elicit similar stress 
      pathways to cisplatin. We therefore reasoned that there may be some role of 
      protein synthesis inhibition in cisplatin ototoxicity. Employing a modification 
      of the bioorthogonal noncanonical amino acid tagging (BONCAT) method, we 
      evaluated the effects of cisplatin on cellular protein synthesis. We show that 
      cisplatin inhibits cellular protein synthesis in organ of Corti explant cultures. 
      Similar to what was found after gentamicin exposure, cisplatin activates both the 
      c-Jun N-terminal kinase (JNK) and mammalian target of rapamycin (mTOR) pathways. 
      In contrast to aminoglycosides, cisplatin also inhibits protein synthesis in all 
      cochlear cell types. We further demonstrate that the multikinase inhibitor 
      sorafenib completely prevents JNK activation, while providing only moderate hair 
      cell protection. Simultaneous stimulation of cellular protein synthesis by 
      insulin, however, significantly improved hair cell survival in culture. The 
      presented data provides evidence for a potential role of protein synthesis 
      inhibition in cisplatin-mediated ototoxicity.
FAU - Nicholas, Brian D
AU  - Nicholas BD
AD  - Department of Neuroscience, University of Virginia, Charlottesville, VA, United 
      States.
FAU - Francis, Shimon
AU  - Francis S
AD  - Department of Neuroscience, University of Virginia, Charlottesville, VA, United 
      States.
FAU - Wagner, Elizabeth L
AU  - Wagner EL
AD  - Department of Neuroscience, University of Virginia, Charlottesville, VA, United 
      States.
FAU - Zhang, Sibo
AU  - Zhang S
AD  - Department of Neuroscience, University of Virginia, Charlottesville, VA, United 
      States.
FAU - Shin, Jung-Bum
AU  - Shin JB
AD  - Department of Neuroscience, University of Virginia, Charlottesville, VA, United 
      States.
LA  - eng
GR  - R01 DC014254/DC/NIDCD NIH HHS/United States
GR  - T32 GM008136/GM/NIGMS NIH HHS/United States
GR  - T32 GM139787/GM/NIGMS NIH HHS/United States
PT  - Journal Article
DEP - 20170927
PL  - Switzerland
TA  - Front Cell Neurosci
JT  - Frontiers in cellular neuroscience
JID - 101477935
PMC - PMC5627031
OTO - NOTNLM
OT  - BONCAT
OT  - Cisplatin
OT  - JNK
OT  - hair cell
OT  - inner ear
OT  - mTOR
OT  - ototoxicity
OT  - protein synthesis
EDAT- 2017/10/17 06:00
MHDA- 2017/10/17 06:01
PMCR- 2017/01/01
CRDT- 2017/10/17 06:00
PHST- 2017/05/30 00:00 [received]
PHST- 2017/09/12 00:00 [accepted]
PHST- 2017/10/17 06:00 [entrez]
PHST- 2017/10/17 06:00 [pubmed]
PHST- 2017/10/17 06:01 [medline]
PHST- 2017/01/01 00:00 [pmc-release]
AID - 10.3389/fncel.2017.00303 [doi]
PST - epublish
SO  - Front Cell Neurosci. 2017 Sep 27;11:303. doi: 10.3389/fncel.2017.00303. 
      eCollection 2017.