title: HSP70 inhibition by the small-molecule 2-phenylethynesulfonamide impairs protein clearance pathways in tumor cells.
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.
authors.affiliation: Department of Genetics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA. leu@mail.med.upenn.edu
authors.forename: J I-Ju
authors.initials: JI
authors.lastname: Leu
authors.forename: Julia
authors.initials: J
authors.lastname: Pimkina
authors.forename: Pooja
authors.initials: P
authors.lastname: Pandey
authors.forename: Maureen E
authors.initials: ME
authors.lastname: Murphy
authors.forename: Donna L
authors.initials: DL
authors.lastname: George
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D016227:Benzoquinones / Q000494:pharmacology; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D018840:HSP70 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D047029:Lactams, Macrocyclic / Q000494:pharmacology; D008247:Lysosomes / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology* / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays
chemical_list: C545662:2-phenylethylenesulfonamide; D016227:Benzoquinones; D018840:HSP70 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D009363:Neoplasm Proteins; D013449:Sulfonamides; C112765:tanespimycin; D046988:Proteasome Endopeptidase Complex