Topically applied Hsp90 inhibitor 17AAG inhibits UVR-induced cutaneous squamous cell carcinomas

Area of Science:

• Oncology
• Dermatology
• Molecular Biology

Background:

• Ultraviolet radiation (UVR) exposure is a primary cause of skin cancer, including cutaneous squamous cell carcinoma (SCC).
• Heat-shock protein 90 (Hsp90) is implicated in cancer development and progression.
• Targeting Hsp90 is a potential strategy for cancer prevention and treatment.

Purpose of the Study:

• To investigate the efficacy of topical 17-(allylamino)-17-demethoxygeldanamycin (17AAG), an Hsp90 inhibitor, in preventing UVR-induced SCC in mice.
• To assess the effects of 17AAG on UVR-induced skin hyperplasia, molecular signaling pathways, and SCC development.

Main Methods:

• 17AAG was applied topically to mouse skin in conjunction with UVR exposure.
• SCC development, latency, incidence, and multiplicity were evaluated in different mouse models.
• UVR-induced hyperplasia, Hsp90β-PKCɛ interaction, and expression of key proteins (Hsp90β, Stat3, Akt, MMP) were analyzed.

Main Results:

• Topical 17AAG significantly increased the latency and decreased the incidence and multiplicity of UVR-induced SCC.
• 17AAG treatment reduced UVR-induced epidermal hyperplasia.
• Inhibition of SCC was associated with decreased Hsp90β-PKCɛ interaction and reduced expression of Hsp90β, Stat3, pAkt, and MMP.

Conclusions:

• Topical Hsp90 inhibitor 17AAG is effective in preventing UVR-induced epidermal hyperplasia and SCC in preclinical models.
• 17AAG demonstrates potential as a preventative agent against UVR-induced skin inflammation and SCC, particularly in high-risk populations.
• The findings support further investigation of topical 17AAG for skin cancer prevention strategies.