Regulator of G protein signaling 17 represents a novel target for treating cisplatin induced hearing loss

Asmita Dhukhwa,Raheem F H Al Aameri,Sandeep Sheth,Leonard Rybak,Debashree Mukherjea,Vickram Ramkumar

doi:10.1038/s41598-021-87387-5

Asmita Dhukhwa, Raheem F H Al Aameri + Show 4 more

Open Access

https://doi.org/10.1038/s41598-021-87387-5

Copy DOI

Abstract

Regulators of G protein signaling (RGS) accelerate the GTPase activity of G proteins to enable rapid termination of the signals triggered by G protein-coupled receptors (GPCRs). Activation of several GPCRs, including cannabinoid receptor 2 (CB2R) and adenosine A1 receptor (A1AR), protects against noise and drug-induced ototoxicity. One such drug, cisplatin, an anticancer agent used to treat various solid tumors, produces permanent hearing loss in experimental animals and in a high percentage of cancer patients who undergo treatments. In this study we show that cisplatin induces the expression of the RGS17 gene and increases the levels of RGS17 protein which contributes to a significant proportion of the hearing loss. Knockdown of RGS17 suppressed cisplatin-induced hearing loss in male Wistar rats, while overexpression of RGS17 alone produced hearing loss in vivo. Furthermore, RGS17 and CB2R negatively regulate the expression of each other. These data suggest that RGS17 mediates cisplatin ototoxicity by uncoupling cytoprotective GPCRs from their normal G protein interactions, thereby mitigating the otoprotective contributions of endogenous ligands of these receptors. Thus, RGS17 represents a novel mediator of cisplatin ototoxicity and a potential therapeutic target for treating hearing loss.

Highlights

Cisplatin is the first FDA-approved platinum drug used for a treatment of solid tumors such as head and neck, bladder, lung, ovarian and testicular cancers[1,2]
Validation of this antibody was done in OCderived UB/OC-1 c ells[35] transiently transfected with RGS17 overexpressing plasmid, which resulted in increased level of RGS17 protein expression as detected via immunofluorescence and Western blotting (Supplementary Fig. S1A–C)
We show that cisplatin increased the expression of RGS17 in the cochlea which was abolished by pretreatment of trans-tympanic JWH-015 prior to cisplatin administration (Fig. 8A). qPCR analysis showed a 4.5 ± 1.0-fold increase in RGS17 with cisplatin, while pretreatment with JWH-015 significantly reduced the fold change to 1.1 ± 0.2

Summary

Introduction

Cisplatin is the first FDA-approved platinum drug used for a treatment of solid tumors such as head and neck, bladder, lung, ovarian and testicular cancers[1,2]. Cisplatin-induced hearing loss is associated with increased cochlear cell death resulting from DNA damage, caspase activation, oxidative stress, inflammation and glutamate excitotoxicity[7,10]. These stressors lead to decrease in endocochlear potential, loss of ribbon synapses, loss of outer hair cells and elevations in ABR thresholds[11,12,13]. Adenosine A1 receptors[14,15,16] and cannabinoid receptor 2 12,17 are expressed in the cochlea, predominantly in the organ of Corti (OC), strial vascularis (SVA) and spiral ganglion neurons (SGN)[12,14,18] Activation of these GPCRs reduced inflammation, oxidative stress and reduced cisplatin-induced ABR threshold s hifts[12,14,19]. Inhibition of RGS17 could enhance the protection mediated by these GPCRs by extending the duration of the receptor-G protein interaction

Methods

Results

Conclusion