Cisplatin-Induced APE2 Overexpression Disrupts MYH9 Function and Causes Hearing Loss

Area of Science:

• Biochemistry
• Ototoxicity Research
• Cancer Therapeutics

Background:

• Cisplatin is a vital chemotherapy drug but causes severe toxicities, notably ototoxicity, particularly in children.
• Current strategies for preventing cisplatin-induced hearing loss (C-HL) are ineffective, and the underlying mechanisms are not fully understood.
• Previous research implicated apurinic/apyrimidinic endonuclease (APE) 2 in cisplatin-induced kidney injury.

Purpose of the Study:

• To investigate the role of APE2 in cisplatin-induced hearing loss (C-HL).
• To elucidate the molecular mechanisms by which APE2 contributes to C-HL.
• To explore APE2 as a potential therapeutic target for preventing C-HL.

Main Methods:

• Assessed APE2 and APE1 expression in murine and human cochlear cells after cisplatin treatment.
• Utilized an inducible, outer hair cell-specific APE2 transgenic mouse model.
• Investigated the interaction between APE2 and MYH9 using biochemical and imaging techniques.
• Examined the effects of APE2 knockdown on mitochondrial function and apoptosis in cochlear cells.
• Analyzed the involvement of the ATR-p53 signaling pathway.

Main Results:

• Cisplatin selectively induced APE2, not APE1, overexpression in outer hair cells.
• APE2 overexpression alone in outer hair cells caused hearing loss, hair cell loss, and stereocilia disorganization.
• A direct interaction between APE2 and MYH9 was identified, with specific binding domains mapped.
• APE2 knockdown preserved mitochondrial metabolism and protected cochlear cells from cisplatin-induced apoptosis.
• Depletion of APE2 activated the ATR-p53 axis, suppressing apoptosis.

Conclusions:

• A noncanonical, APE2-dependent mechanism drives cisplatin-induced hearing loss.
• APE2 interacts with MYH9 and disrupts mitochondrial integrity, leading to cochlear cell death.
• Targeting APE2 presents a promising novel therapeutic strategy for preventing C-HL.