Abstract
Cisplatin is a widely used chemotherapeutic drug for treating various solid tumors. Ototoxicity is a major dose-limiting side effect of cisplatin, which causes progressive and irreversible sensorineural hearing loss. Here, we examined the protective effects of glucose-related protein (GRP) 78 and 94, also identified as endoplasmic reticulum (ER) chaperone proteins, on cisplatin-induced ototoxicity. Treating murine auditory cells (HEI-OC1) with 25 μM cisplatin for 24 h increased cell death resulting from excessive intracellular reactive oxygen species (ROS) accumulation and caspase-involved apoptotic signaling pathway activation with subsequent DNA fragmentation. GRP78 and GRP94 expression was increased in cells treated with 3 nM thapsigargin or 0.1 μg/mL tunicamycin for 24 h, referred to as mild ER stress condition. This condition, prior to cisplatin exposure, attenuated cisplatin-induced ototoxicity. The involvement of GRP78 and GRP94 induction was demonstrated by the knockdown of GRP78 or GRP94 expression using small interfering RNAs, which abolished the protective effect of mild ER stress condition on cisplatin-induced cytotoxicity. These results indicated that GRP78 and GRP94 induction plays a protective role in remediating cisplatin-ototoxicity.
Highlights
Hearing loss, known as hearing impairment, is generally classified into conductive and sensorineural hearing loss
These results indicated that GRP78 and GRP94 induction plays a protective role in remediating cisplatin-ototoxicity
We examined the protective effects of GRP78 and GRP94 on cisplatin-induced ototoxicity
Summary
Known as hearing impairment, is generally classified into conductive and sensorineural hearing loss. The latter is caused by several risk factors, including acoustic trauma, aging, ototoxic drug use, autoimmune disease, infection, and genetic disorders. Hearing loss is commonly associated with the loss of auditory hair cells in the cochlea, which is irreversible due to its inability to regenerate irreparable hair cell damage [1]. Various commonly used drugs have ototoxic properties that damage the cochlea or auditory nerve and vestibular system and are referred to as drug-induced hearing loss (DIHL). Further accumulation of ototoxic medication may lead to permanent destruction of the sensory hair cells and, concomitantly, permanent hearing loss [2]
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