A small molecule inhibitor of inducible heat shock protein 70

Mol Cell. 2009 Oct 9;36(1):15-27. doi: 10.1016/j.molcel.2009.09.023.

Abstract

The multifunctional, stress-inducible molecular chaperone HSP70 has important roles in aiding protein folding and maintaining protein homeostasis. HSP70 expression is elevated in many cancers, contributing to tumor cell survival and resistance to therapy. We have determined that a small molecule called 2-phenylethynesulfonamide (PES) interacts selectively with HSP70 and leads to a disruption of the association between HSP70 and several of its cochaperones and substrate proteins. Treatment of cultured tumor cells with PES promotes cell death that is associated with protein aggregation, impaired autophagy, and inhibition of lysosomal function. Moreover, this small molecule is able to suppress tumor development and enhance survival in a mouse model of Myc-induced lymphomagenesis. The data demonstrate that PES disrupts actions of HSP70 in multiple cell signaling pathways, offering an opportunity to better understand the diverse functions of this molecular chaperone and also to aid in the development of new cancer therapies.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • Apoptotic Protease-Activating Factor 1 / metabolism
  • Autophagy / drug effects
  • Caspases / metabolism
  • Cathepsin L / metabolism
  • Cell Death / drug effects
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • DNA-Binding Proteins / metabolism
  • HSP40 Heat-Shock Proteins / metabolism
  • HSP70 Heat-Shock Proteins / antagonists & inhibitors*
  • HSP70 Heat-Shock Proteins / genetics
  • HSP70 Heat-Shock Proteins / metabolism
  • Humans
  • Lymphoma / pathology
  • Lymphoma / prevention & control
  • Lysosomes / drug effects
  • Lysosomes / metabolism
  • Mice
  • Mice, Inbred Strains
  • Mice, Transgenic
  • Microtubule-Associated Proteins / metabolism
  • NF-kappa B / metabolism
  • Protein Binding / drug effects
  • Protein Binding / physiology
  • Protein Interaction Domains and Motifs
  • Protein Multimerization / drug effects
  • Sequestosome-1 Protein
  • Sulfonamides / metabolism
  • Sulfonamides / pharmacology*
  • Sulfonamides / therapeutic use
  • Transcription Factors / metabolism
  • Tumor Suppressor Protein p53 / metabolism
  • Ubiquitin-Protein Ligases / metabolism

Substances

  • 2-phenylethylenesulfonamide
  • APAF1 protein, human
  • Adaptor Proteins, Signal Transducing
  • Apoptotic Protease-Activating Factor 1
  • BCL2-associated athanogene 1 protein
  • DNA-Binding Proteins
  • DNAJB1 protein, human
  • HSP40 Heat-Shock Proteins
  • HSP70 Heat-Shock Proteins
  • HSPA1A protein, human
  • Microtubule-Associated Proteins
  • NF-kappa B
  • SQSTM1 protein, human
  • Sequestosome-1 Protein
  • Sulfonamides
  • Transcription Factors
  • Tumor Suppressor Protein p53
  • light chain 3, human
  • STUB1 protein, human
  • Ubiquitin-Protein Ligases
  • Caspases
  • CTSL protein, human
  • Cathepsin L