Cisplatin-induced ototoxicity involves interaction of PRMT3 and cannabinoid system

• Published in: Archives of toxicology Vol. 93; no. 8; pp. 2335 - 2346
• Main Authors: Lim, Je-Oh, Ko, Je-Won, Shin, Na-Rae, Jung, Tae-Yang, Moon, Changjong, Kim, Hyoung-Chin, Shin, In-Sik, Kim, Jong-Choon
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.08.2019; Springer Nature B.V
• Subjects: Adenosine; Adenosine diphosphate; Apoptosis; Arginine; Biomedical and Life Sciences; Biomedicine; Cannabinoids; Caspase; Caspase-3; Caspase-9; Chemotherapy; Cisplatin; Cytosine; Endocannabinoid system; Endoplasmic reticulum; Environmental Health; Fatty acids; Fatty-acid amide hydrolase; Homology; Hydrolase; Mice; Occupational Medicine/Industrial Medicine; Organ of Corti; Organ Toxicity and Mechanisms; Ototoxicity; p53 Protein; Pharmacology/Toxicology; Protein arginine methyltransferase; Proteins; Ribose; Signaling; Stress; Thymidine; Mechanism of action; PRMT; Cisplatin; Ototoxicity; Cannabinoid system
• ISSN: 0340-5761; 1432-0738
• DOI: 10.1007/s00204-019-02507-5

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.