TY - JOUR
T1 - Regulation of Tumor Cell Mitochondrial Homeostasis by an Organelle-Specific Hsp90 Chaperone Network
AU - Kang, Byoung Heon
AU - Plescia, Janet
AU - Dohi, Takehiko
AU - Rosa, Jack
AU - Doxsey, Stephen J.
AU - Altieri, Dario C.
PY - 2007/10/19
Y1 - 2007/10/19
N2 - 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.
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.
UR - http://www.scopus.com/inward/record.url?scp=35348887850&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=35348887850&partnerID=8YFLogxK
U2 - 10.1016/j.cell.2007.08.028
DO - 10.1016/j.cell.2007.08.028
M3 - Article
C2 - 17956728
AN - SCOPUS:35348887850
SN - 0092-8674
VL - 131
SP - 257
EP - 270
JO - Cell
JF - Cell
IS - 2
ER -