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Heat Shock Protein 60 Regulation of the Mitochondrial Permeability Transition Pore in Tumor Cells

2010; American Association for Cancer Research; Volume: 70; Issue: 22 Linguagem: Inglês

10.1158/0008-5472.can-10-2225

1538-7445

Jagadish C. Ghosh, Markus D. Siegelin, Takehiko Dohi, Dario C. Altieri,

ATP Synthase and ATPases Research

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.