Cisplatin-induced hair cell death requires STAT1 and is attenuated by epigallocatechin gallate

Nicole Schmitt, Edwin W. Rubel, Neil M. Nathanson

Research output: Contribution to journalArticle

Abstract

Cisplatin is a chemotherapy drug that frequently causes auditory impairment due to the death of mechanosensory hair cells. Cisplatin ototoxicity may result from oxidative stress, DNA damage, and inflammatory cytokines. The transcription factor STAT1, an important mediator of cell death, can regulate all of these processes in other cell types. We used cultured utricles from mature Swiss Webster mice to investigate the role of STAT 1 in cisplatin-induced hair cell death. We show that STAT1 phosphorylation is an early event in both hair cells and support cells after exposure of utricles to cisplatin. STAT1 phosphorylation peaked after 4 h of cisplatin exposure and returned to control levels by 8 h of exposure. The STAT1 inhibitor epigallocatechin gallate (EGCG) attenuated STAT1 phosphorylation in cisplatintreated utricles and resulted in concentration-dependent increases in hair cell survival at 24 h postexposure. Furthermore, we show that utricular hair cells from STAT1-deficient mice are resistant to cisplatin toxicity. EGCG failed to provide additional protection from cisplatin in STAT1-deficient mice, further supporting the hypothesis that the protective effects of EGCG are due to its inhibition of STAT1. Treatment with IFN-γ, which also causes STAT1 activation, also induced hair cell death in wild-type but not STAT1-deficient mice. These results show that STAT1 is required for maximal cisplatin-induced hair cell death in the mouse utricle and suggest that treatment with EGCG may be a useful strategy for prevention of cisplatin ototoxicity.

Original languageEnglish (US)
Pages (from-to)3843-3851
Number of pages9
JournalJournal of Neuroscience
Volume29
Issue number12
DOIs
StatePublished - Mar 25 2009
Externally publishedYes

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Cisplatin
Cell Death
Saccule and Utricle
Phosphorylation
STAT1 Transcription Factor
epigallocatechin gallate
DNA Damage
Cell Survival
Oxidative Stress
Cytokines
Drug Therapy
Therapeutics
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Neuroscience(all)
  • Medicine(all)

Cite this

Cisplatin-induced hair cell death requires STAT1 and is attenuated by epigallocatechin gallate. / Schmitt, Nicole; Rubel, Edwin W.; Nathanson, Neil M.

In: Journal of Neuroscience, Vol. 29, No. 12, 25.03.2009, p. 3843-3851.

Research output: Contribution to journalArticle

Schmitt, Nicole ; Rubel, Edwin W. ; Nathanson, Neil M. / Cisplatin-induced hair cell death requires STAT1 and is attenuated by epigallocatechin gallate. In: Journal of Neuroscience. 2009 ; Vol. 29, No. 12. pp. 3843-3851.
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