AUY922 induces retinal toxicity through attenuating TRPM1.

Area of Science:

• Oncology
• Ophthalmology
• Molecular Biology

Background:

• Ocular adverse events are common dose-limiting toxicities in cancer patients treated with HSP90 inhibitors like AUY922.
• The specific pathology and molecular mechanisms of AUY922-induced retinal toxicity are not well understood.

Purpose of the Study:

• To investigate the pathological and molecular mechanisms of AUY922-induced retinal toxicity.
• To identify key molecular players involved in AUY922 retinal damage.

Main Methods:

• Proteomic profiling (iTRAQ) and pathway analysis were used to assess AUY922's impact on mouse retinas and cell lines.
• Immunohistochemistry, TUNEL assay, MTT assay, and western blot analysis were employed to evaluate retinal damage and apoptosis.
• Co-immunoprecipitation and RNAseq were used to characterize the interaction between TRPM1 and HSP90 and analyze TRPM1-regulated gene expression.

Main Results:

• AUY922 treatment induced retinal damage, apoptosis, and dysregulation of photoreceptor and RPE layers, with reduced TRPM1 expression.
• Proteomic analysis revealed enrichment of pathways related to stress responses, apoptosis, ROS production, and cell adhesion in AUY922-treated cells.
• TRPM1 was identified as an HSP90 client, and its reduced expression by AUY922 was linked to disruption of the CDC37-HSP90 chaperone complex, mediating cytotoxicity.

Conclusions:

• AUY922 induces retinal toxicity in vivo through mechanisms involving TRPM1.
• TRPM1 is an HSP90 client protein crucial for photoreceptor morphology and function.
• TRPM1 plays a mediating role in the cytotoxicity induced by AUY922, highlighting it as a potential therapeutic target or biomarker.