Article

HSP70 inhibition by the small-molecule 2-phenylethynesulfonamide impairs protein clearance pathways in tumor cells.

Department of Genetics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
Molecular Cancer Research (impact factor: 4.29). 06/2011; 9(7):936-47. DOI:10.1158/1541-7786.MCR-11-0019 pp.936-47
Source: PubMed

ABSTRACT The evolutionarily conserved stress-inducible HSP70 molecular chaperone plays a central role in maintaining protein quality control in response to various forms of stress. Constitutively elevated HSP70 expression is a characteristic of many tumor cells and contributes to their survival. We recently identified the small-molecule 2-phenylethyenesulfonamide (PES) as a novel HSP70 inhibitor. Here, we present evidence that PES-mediated inhibition of HSP70 family proteins in tumor cells results in an impairment of the two major protein degradation systems, namely, the autophagy-lysosome system and the proteasome pathway. HSP70 family proteins work closely with the HSP90 molecular chaperone to maintain the stability and activities of their many client proteins, and PES causes a disruption in the HSP70/HSP90 chaperone system. As a consequence, many cellular proteins, including known HSP70/HSP90 substrates, accumulate in detergent-insoluble cell fractions, indicative of aggregation and functional inactivation. Overall, PES simultaneously disrupts several cancer critical survival pathways, supporting the idea of targeting HSP70 as a potential approach for cancer therapeutics.

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Keywords

autophagy-lysosome system
 
cancer critical survival pathways
 
cancer therapeutics
 
cellular proteins
 
client proteins
 
detergent-insoluble cell fractions
 
evolutionarily conserved stress-inducible HSP70 molecular chaperone
 
functional inactivation
 
HSP70 expression
 
HSP70 family proteins
 
HSP70 family proteins work
 
HSP70/HSP90 chaperone system
 
HSP70/HSP90 substrates
 
HSP90 molecular chaperone
 
novel HSP70 inhibitor
 
PES causes
 
PES-mediated inhibition
 
protein quality control
 
small-molecule 2-phenylethyenesulfonamide
 
tumor cells results
 

Julia I-Ju Leu