Cisplatin-induced ototoxicity involves interaction of PRMT3 and cannabinoid system

Area of Science:

• Ototoxicity research
• Molecular biology
• Neuroscience

Background:

• Cisplatin is a common chemotherapy agent with ototoxicity as a significant side effect.
• The roles of protein arginine methyltransferases (PRMTs) and the cannabinoid system in cisplatin-induced ototoxicity are not fully understood.

Purpose of the Study:

• To investigate the involvement of PRMTs and the cannabinoid system in cisplatin-induced ototoxicity.
• To elucidate the molecular mechanisms underlying cisplatin's damaging effects on auditory cells.

Main Methods:

• Utilized House Ear Institute-Organ of Corti 1 (HEI-OC1) cells for in vitro studies.
• Assessed endoplasmic reticulum (ER) stress and apoptosis markers (caspase-3, -9, PARP, p53).
• Performed in vivo experiments in C57BL/6 mice treated with cisplatin.

Main Results:

• Cisplatin induced ER stress, apoptosis, and upregulated PRMT3, PRMT4, and fatty acid amide hydrolase 1 (FAAH1) in HEI-OC1 cells.
• Overexpression of PRMT3/4 or FAAH1 exacerbated ER stress and apoptosis; knockdown had opposite effects.
• PRMT3 binding with FAAH1 increased upon cisplatin treatment; cannabinoid receptor agonist and FAAH inhibitor mitigated ototoxicity.
• PRMT3 and PRMT4 were upregulated in the mouse organ of Corti post-cisplatin treatment.

Conclusions:

• Cisplatin-induced ototoxicity is associated with PRMT3, PRMT4, and the cannabinoid system.
• PRMT3 interacts with FAAH1, mediating cisplatin-induced ototoxicity through ER stress and apoptosis pathways.
• Targeting the PRMT3-FAAH1 interaction may offer a strategy to prevent cisplatin-induced hearing loss.