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Arch Toxicol. 2019 Aug;93(8):2335-2346. doi: 10.1007/s00204-019-02507-5. Epub 2019 Jun 29.

Cisplatin-induced ototoxicity involves interaction of PRMT3 and cannabinoid system.

Author information

1
College of Veterinary Medicine (BK21 Plus Project Team), Chonnam National University, Gwangju, 61186, Republic of Korea.
2
Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology, Cheongju, 28116, Republic of Korea.
3
College of Veterinary Medicine (BK21 Plus Project Team), Chonnam National University, Gwangju, 61186, Republic of Korea. dvmmk79@gmail.com.
4
College of Veterinary Medicine (BK21 Plus Project Team), Chonnam National University, Gwangju, 61186, Republic of Korea. toxkim@jnu.ac.kr.

Abstract

This study investigated whether protein arginine methyltransferase (PRMT) and the cannabinoid system are involved in cisplatin-induced ototoxicity. Cisplatin increased cytosine-cytosine-adenosine-adenosine-thymidine-enhancer-binding protein homologous protein expression. This effect is indicative of an increase in endoplasmic reticulum (ER) stress, and apoptosis signaling including cleavage of caspase-3, caspase-9, poly-adenosine diphosphate-ribose polymerase, and phospho-p53, as well as expression of PRMT3, PRMT4 and fatty acid amide hydrolase (FAAH)1 in House Ear Institute-Organ of Corti 1 (HEI-OC1) cells. In addition, overexpression of PRMT3 or PRMT4 increased the expression of FAAH1 expression, apoptosis, and ER stress signaling in HEI-OC1 cells, whereas PRMT3 or PRMT4 knockdown had the opposite effect. Furthermore, overexpression of FAAH1 increased apoptosis and ER stress, but expression of the PRMTs was unchanged. In addition, a cannabinoid 1 receptor agonist and FAAH inhibitor attenuated apoptosis and ER stress, while cisplatin increased the binding of PRMT3 with FAAH1. In the in vivo experiments, cisplatin was injected intraperitoneally at 6 mg/kg/day into C57BL/6 mice, and 7 days later, this study confirmed that PRMT3 and PRMT4 were upregulated in the organ of Corti of the mice. These results indicate that cisplatin-induced ototoxicity was correlated with PRMT3, PRMT4 and the cannabinoid system, and PRMT3 binding with FAAH1 was increased by cisplatin in HEI-OC1 cells. Therefore, this study suggests that PRMT3 mediates cisplatin-induced ototoxicity via interaction with FAAH1 in vitro and in vivo.

KEYWORDS:

Cannabinoid system; Cisplatin; Mechanism of action; Ototoxicity; PRMT

PMID:
31256211
DOI:
10.1007/s00204-019-02507-5

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