Regulation of tumor cell mitochondrial homeostasis by an organelle-specific Hsp90 chaperone network.
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.
Kang
Byoung Heon
BH
Department of Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Plescia
Janet
J
Dohi
Takehiko
T
Rosa
Jack
J
Doxsey
Stephen J
SJ
Altieri
Dario C
DC
D000818:Animals; D017209:Apoptosis; D016227:Benzoquinones / Q000138:chemical synthesis / Q000494:pharmacology; D045744:Cell Line, Tumor; D002463:Cell Membrane Permeability; D000081406:Peptidyl-Prolyl Isomerase F; D021983:Cyclophilins / Q000378:metabolism; D015195:Drug Design; D018841:HSP90 Heat-Shock Proteins / Q000502:physiology*; D006706:Homeostasis; D006801:Humans; D007074:Immunoglobulin G; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology*; D047029:Lactams, Macrocyclic / Q000138:chemical synthesis / Q000494:pharmacology; D008558:Melphalan; D053078:Membrane Potential, Mitochondrial; D051379:Mice; D008928:Mitochondria / Q000502:physiology*; D009928:Organ Specificity; D015388:Organelles / Q000502:physiology*; D010446:Peptide Fragments / Q000494:pharmacology; D017510:Protein Folding
D016227:Benzoquinones; D000081406:Peptidyl-Prolyl Isomerase F; D018841:HSP90 Heat-Shock Proteins; D007074:Immunoglobulin G; D047908:Intracellular Signaling Peptides and Proteins; D047029:Lactams, Macrocyclic; C000631446:PPIF protein, mouse; D010446:Peptide Fragments; C111893:TGFBRAP1 protein, human; C051713:antineoplastic agent K 18; C503112:shepherdin; C112765:tanespimycin; D021983:Cyclophilins; D008558:Melphalan