Aptamer-mediated targeted approach to disrupt oncogenic HSP90α

Area of Science:

• Biochemistry
• Molecular Biology
• Oncology

Background:

• Cytosolic Heat Shock Protein 90 (HSP90) has two main isoforms: HSP90α and HSP90β.
• HSP90α is significantly upregulated in cancer and stress conditions, supporting cancer cell proliferation.
• Current HSP90 inhibitors lack isoform specificity, hindering clinical application.

Purpose of the Study:

• To develop RNA aptamers that selectively bind and inhibit HSP90α.
• To investigate the anti-cancer potential of these aptamers.
• To assess the therapeutic implications of isoform-specific HSP90α inhibition.

Main Methods:

• Selection of RNA aptamers from a randomized oligonucleotide library.
• Affinity-based binding assays to compare aptamer binding to HSP90α and HSP90β.
• Assays to measure ATPase activity inhibition.
• Cell migration assays using MCF7 breast cancer cells.
• Western blot analysis to assess client protein expression.
• Cell viability assays on cancer and healthy cells.
• Apoptosis assays.

Main Results:

• Selected RNA aptamers exhibited significantly higher affinity for HSP90α compared to HSP90β.
• Aptamers inhibited HSP90α ATPase activity.
• Aptamer treatment decreased MCF7 breast cancer cell migration.
• Expression of HSP90α-specific client proteins was significantly reduced.
• Aptamers induced significant lethality in cancer cells but not in healthy cells, via apoptosis.
• Apoptosis was confirmed as the mechanism of cell death.

Conclusions:

• RNA aptamers can be specifically selected to target HSP90α.
• These aptamers inhibit HSP90α function, leading to reduced cancer cell proliferation and migration.
• Aptamers demonstrate selective toxicity towards cancer cells, offering a potential therapeutic strategy.
• Aptamers represent a promising alternative to traditional anti-cancer drugs for metastasis prevention.