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Published on: July 21, 2021
Exploiting the HSP60/10 chaperonin system as a chemotherapeutic target for colorectal cancer
Anne-Marie Ray1, Nilshad Salim1, Mckayla Stevens1
1Indiana University School of Medicine, Department of Biochemistry and Molecular Biology, 635 Barnhill Dr., Indianapolis, IN 46202, United States.
Abstract:
Over the past few decades, an increasing variety of molecular chaperones have been investigated for their role in tumorigenesis and as potential chemotherapeutic targets; however, the 60 kDa Heat Shock Protein (HSP60), along with its HSP10 co-chaperone, have received little attention in this regard. In the present study, we investigated two series of our previously developed inhibitors of the bacterial homolog of HSP60/10, called GroEL/ES, for their selective cytotoxicity to cancerous over non-cancerous colorectal cells. We further developed a third "hybrid" series of analogs to identify new candidates with superior properties than the two parent scaffolds. Using a series of well-established HSP60/10 biochemical screens and cell-viability assays, we identified 24 inhibitors (14%) that exhibited > 3-fold selectivity for targeting colorectal cancer over non-cancerous cells. Notably, cell viability EC50 results correlated with the relative expression of HSP60 in the mitochondria, suggesting a potential for this HSP60-targeting chemotherapeutic strategy as emerging evidence indicates that HSP60 is up-regulated in colorectal cancer tumors. Further examination of five lead candidates indicated their ability to inhibit the clonogenicity and migration of colorectal cancer cells. These promising results are the most thorough analysis and first reported instance of HSP60/10 inhibitors being able to selectively target colorectal cancer cells and highlight the potential of the HSP60/10 chaperonin system as a viable chemotherapeutic target.
Insights
New inhibitors targeting Heat Shock Protein 60 (HSP60) and its co-chaperone HSP10 show selective killing of colorectal cancer cells. This suggests HSP60/10 chaperonins are promising targets for novel cancer therapies.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Molecular chaperones, including Heat Shock Protein 60 (HSP60) and its co-chaperone HSP10, are increasingly recognized for their roles in cancer development.
- Despite their potential, HSP60 and HSP10 have been relatively understudied as chemotherapeutic targets, particularly in colorectal cancer.
Purpose of the Study:
- To investigate the selective cytotoxicity of previously developed HSP60/10 inhibitors against colorectal cancer cells.
- To develop novel "hybrid" analogs of HSP60/10 inhibitors with potentially superior anti-cancer properties.
- To evaluate the potential of targeting the HSP60/10 chaperonin system as a chemotherapeutic strategy for colorectal cancer.
Main Methods:
- Utilized established HSP60/10 biochemical assays and cell-viability assays.
- Screened two series of existing inhibitors and a newly developed hybrid series against cancerous and non-cancerous colorectal cells.
- Assessed the correlation between inhibitor efficacy and HSP60 expression levels in cancer cell mitochondria.
Main Results:
- Identified 24 inhibitors (14%) demonstrating greater than 3-fold selectivity for colorectal cancer cells over non-cancerous cells.
- Observed a correlation between cell viability (EC50) and mitochondrial HSP60 expression, supporting HSP60 as a target.
- Five lead inhibitor candidates effectively inhibited colorectal cancer cell clonogenicity and migration.
Conclusions:
- HSP60/10 inhibitors can selectively target and reduce the viability of colorectal cancer cells.
- The HSP60/10 chaperonin system represents a viable and promising therapeutic target for colorectal cancer.
- These findings provide the most comprehensive analysis to date of HSP60/10 inhibitors in selective colorectal cancer targeting.
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