Heat shock protein 60 regulation of the mitochondrial permeability transition pore in tumor cells

Cancer Res. 2010 Nov 15;70(22):8988-93. doi: 10.1158/0008-5472.CAN-10-2225. Epub 2010 Oct 26.

Abstract

Mitochondrial apoptosis plays a critical role in tumor maintenance and dictates the response to therapy in vivo; however, the regulators of this process are still largely elusive. Here, we show that the molecular chaperone heat shock protein 60 (Hsp60) directly associates with cyclophilin D (CypD), a component of the mitochondrial permeability transition pore. This interaction occurs in a multichaperone complex comprising Hsp60, Hsp90, and tumor necrosis factor receptor-associated protein-1, selectively assembled in tumor but not in normal mitochondria. Genetic targeting of Hsp60 by siRNA triggers CypD-dependent mitochondrial permeability transition, caspase-dependent apoptosis, and suppression of intracranial glioblastoma growth in vivo. Therefore, Hsp60 is a novel regulator of mitochondrial permeability transition, contributing to a cytoprotective chaperone network that antagonizes CypD-dependent cell death in tumors.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Blotting, Western
  • Caspases / metabolism
  • Cell Line, Tumor
  • Cell Proliferation
  • Cells, Cultured
  • Chaperonin 60 / genetics
  • Chaperonin 60 / metabolism*
  • Cyclophilin D
  • Cyclophilins / metabolism*
  • Flow Cytometry
  • HCT116 Cells
  • HEK293 Cells
  • HSP90 Heat-Shock Proteins / metabolism
  • Humans
  • Kaplan-Meier Estimate
  • Mice
  • Mice, Nude
  • Mitochondrial Membrane Transport Proteins / metabolism*
  • Neoplasms / genetics
  • Neoplasms / metabolism*
  • Neoplasms / pathology
  • Neoplasms, Experimental / genetics
  • Neoplasms, Experimental / metabolism
  • Neoplasms, Experimental / pathology
  • Protein Binding
  • RNA Interference
  • Transplantation, Heterologous

Substances

  • Chaperonin 60
  • Cyclophilin D
  • HSP90 Heat-Shock Proteins
  • Mitochondrial Membrane Transport Proteins
  • PPIF protein, mouse
  • TRAP1 protein, human
  • mitochondrial permeability transition pore
  • Caspases
  • Cyclophilins