Regulation of Tumor Cell Mitochondrial Homeostasis by an Organelle-Specific Hsp90 Chaperone Network

Byoung Heon Kang, Janet Plescia, Takehiko Dohi, Jack Rosa, Stephen J. Doxsey, Dario C. Altieri

Research output: Contribution to journalArticle

287 Citations (Scopus)

Abstract

Molecular chaperones, especially members of the heat shock protein 90 (Hsp90) family, are thought to promote tumor cell survival, but this function is not well understood. Here, we show that mitochondria of tumor cells, but not most normal tissues, contain Hsp90 and its related molecule, TRAP-1. These chaperones interact with Cyclophilin D, an immunophilin that induces mitochondrial cell death, and antagonize its function via protein folding/refolding mechanisms. Disabling this pathway using novel Hsp90 ATPase antagonists directed to mitochondria causes sudden collapse of mitochondrial function and selective tumor cell death. Therefore, Hsp90-directed chaperones are regulators of mitochondrial integrity, and their organelle-specific antagonists may provide a previously undescribed class of potent anticancer agents.

Original languageEnglish (US)
Pages (from-to)257-270
Number of pages14
JournalCell
Volume131
Issue number2
DOIs
StatePublished - Oct 19 2007

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HSP90 Heat-Shock Proteins
Organelles
Specific heat
Tumors
Homeostasis
Cells
Mitochondria
Cell death
Neoplasms
Cell Death
Immunophilins
Protein Refolding
Protein folding
Molecular Chaperones
Protein Folding
Antineoplastic Agents
Adenosine Triphosphatases
Cell Survival
Tissue
Molecules

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Kang, Byoung Heon ; Plescia, Janet ; Dohi, Takehiko ; Rosa, Jack ; Doxsey, Stephen J. ; Altieri, Dario C. / Regulation of Tumor Cell Mitochondrial Homeostasis by an Organelle-Specific Hsp90 Chaperone Network. In: Cell. 2007 ; Vol. 131, No. 2. pp. 257-270.
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Regulation of Tumor Cell Mitochondrial Homeostasis by an Organelle-Specific Hsp90 Chaperone Network. / Kang, Byoung Heon; Plescia, Janet; Dohi, Takehiko; Rosa, Jack; Doxsey, Stephen J.; Altieri, Dario C.

In: Cell, Vol. 131, No. 2, 19.10.2007, p. 257-270.

Research output: Contribution to journalArticle

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AB - Molecular chaperones, especially members of the heat shock protein 90 (Hsp90) family, are thought to promote tumor cell survival, but this function is not well understood. Here, we show that mitochondria of tumor cells, but not most normal tissues, contain Hsp90 and its related molecule, TRAP-1. These chaperones interact with Cyclophilin D, an immunophilin that induces mitochondrial cell death, and antagonize its function via protein folding/refolding mechanisms. Disabling this pathway using novel Hsp90 ATPase antagonists directed to mitochondria causes sudden collapse of mitochondrial function and selective tumor cell death. Therefore, Hsp90-directed chaperones are regulators of mitochondrial integrity, and their organelle-specific antagonists may provide a previously undescribed class of potent anticancer agents.

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