Bis-aryl-α,β-unsaturated ketone (ABK) chaperonin inhibitors exhibit selective cytotoxicity to colorectal cancer cells that correlates with levels of aberrant HSP60 in the cytosol.

Abstract

While many studies have established the importance of protein homeostasis in tumor progression, little effort has been made to examine the therapeutic potential of targeting the HSP60 chaperonin system. In healthy cells, HSP60 is localized to the mitochondrial matrix; however, emerging evidence indicates HSP60 can be over-expressed and mis-localized to the cytosol of cancer cells, which is hypothesized to promote tumor cell survival and proliferation. This opens a potential avenue to selectively target the aberrant HSP60 in the cytosol as a chemotherapeutic strategy. In the present work, we examined a series of bis-aryl-α,β-unsaturated ketone (ABK) HSP60 inhibitors for their ability to selectively target cancerous vs non-cancerous colon and intestine cells. We found that lead analogs inhibited migration and clonogenicity of cancer cells, with cytotoxicity correlating with the level of aberrant HSP60 in the cytosol.

• Authors: Siddhi Chitre, Anne-Marie Ray, Mckayla Stevens, Emma H Doud, Hope Liechty, Alex Washburn, Katelyn Tepper, Jared Sivinski, Heather M O'Hagan, Millie M Georgiadis, Eli Chapman, Steven M Johnson
• Journal: Bioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 75 Pg. 117072 (12 01 2022) ISSN: 1464-3391 [Electronic] England
• PMID: 36356534 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2022 Elsevier Ltd. All rights reserved.

Chemical References

• Chaperonins
• Chaperonin 60
• Chaperonin 10

Topics

• Humans
• Cytosol (metabolism)
• Chaperonins
• Mitochondria (metabolism)
• Colorectal Neoplasms (drug therapy, metabolism)
• Chaperonin 60 (metabolism)
• Chaperonin 10 (metabolism)