2-phenylethylenesulfonamide and Neoplasms

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.

Topics: Animals; Autophagy; Benzoquinones; Cell Line, Tumor; Female; Gene Expression Regulation, Neoplastic; HSP70 Heat-Shock Proteins; Humans; Lactams, Macrocyclic; Lysosomes; Mice; Mice, Nude; Neoplasm Proteins; Neoplasms; Proteasome Endopeptidase Complex; Sulfonamides; Xenograft Model Antitumor Assays

Topics: HSP72 Heat-Shock Proteins; Humans; Neoplasms; Sulfonamides