Journal
ANTIOXIDANTS & REDOX SIGNALING
Volume 30, Issue 11, Pages 1389-1410Publisher
MARY ANN LIEBERT, INC
DOI: 10.1089/ars.2017.7288
Keywords
spiral ganglion neuron; Wnt/beta-catenin signaling; cisplatin; TIGAR; reactive oxygen species
Funding
- National Natural Science Foundation of China [81600803, 81570918, 81200744, 81622013, 81470692, 81500790, 81570921, 31500852, 31501194]
- National Key R&D Program of China [2015CB965000, 2017YFA0103903]
- Projects of Medical and Heath Technology Development Program of Shandong Province [2016WS0450]
- Natural Science Foundation of Jiangsu Province [BK20150022, BK20150598, BK20160125]
- Boehringer Ingelheim Pharma GmbH
- Yingdong Huo Education Foundation
- Fundamental Research Funds for the Central Universities
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Aims: Cisplatin can damage spiral ganglion neurons (SGNs) and cause sensorineural hearing loss. Wnt activation protects against neomycin-induced hair cell damage in the mouse cochlea, but the role of Wnt signaling in protecting SGNs from cisplatin treatment has not yet been elucidated. This study was designed to investigate the neuroprotective effects of Wnt signaling against cisplatin-induced SGN damage. Results: First, we found that Wnt signaling was activated in SGNs after cisplatin treatment. Next, we discovered that overexpression (OE) of Wnt signaling in SGNs reduced cisplatin-induced SGN loss by inhibiting caspase-associated apoptosis, thus preventing the loss of SGN function after cisplatin treatment. In contrast, inhibition of Wnt signaling increased apoptosis, made SGNs more vulnerable to cisplatin treatment, and exacerbated hearing loss. TP53-induced glycolysis and apoptosis regulator (TIGAR), which scavenges intracellular reactive oxygen species (ROS), was upregulated in SGNs in response to cisplatin administration. Wnt/beta-catenin activation increased TIGAR expression and reduced ROS level, while inhibition of Wnt/beta-catenin in SGNs reduced TIGAR expression and increased the ROS level. Moreover, OE of TIGAR reduced ROS and decreased caspase 3 expression, as well as increased the survival of SGNs in Wnt-inhibited SGNs. Finally, antioxidant treatment rescued the more severe SGN loss induced by beta-catenin deficiency after cisplatin treatment. Innovation and Conclusion: This study is the first to indicate that Wnt signaling activates TIGAR and protects SGNs against cisplatin-induced damage through the inhibition of oxidative stress and apoptosis in SGNs, and this might offer novel therapeutic targets for the prevention of SGN injury.
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