Aptamer-mediated targeted approach to disrupt oncogenic HSP90α

Among the cytosolic isoforms of HSP90, HSP90α (the inducible isoform) has been observed to be significantly upregulated in both cancer and stress conditions. HSP90α client proteins are required for the proliferation of cancer cells. The inability of HSP90 inhibitors to recognize and bind to specific isoforms of the protein is a major reason for their failure to reach the clinic. In this work, RNA aptamers were selected from a diverse, randomized oligonucleotide library. These were able to bind to HSP90α with significantly higher affinity than HSP90β and inhibit ATPase activity. The two isoforms differ in just two amino acids in their ATP-binding domains. The presence of the aptamers led to decrease in migration of MCF7 breast cancer cells. Significant reduction in the expression of an HSP90α- but not HSP90β-specific client protein was also observed. Aptamers showed significant lethality only on cancer cells, but not on healthy cells. Cell death occurred by apoptosis. Unlike traditional anti-cancer drugs which are inherently toxic and cannot be administered regularly, aptamers offer a promising alternative for prevention of metastasis.