TY - JOUR
T1 - Hsp27 inhibits release of mitochondrial protein Smac in multiple myeloma cells and confers dexamethasone resistance
AU - Chauhan, Dharminder
AU - Li, Guilan
AU - Hideshima, Teru
AU - Podar, Klaus
AU - Mitsiades, Constantine
AU - Mitsiades, Nicholas
AU - Catley, Laurence
AU - Tai, Yu Tzu
AU - Hayashi, Toshiaki
AU - Shringarpure, Reshma
AU - Burger, Renate
AU - Munshi, Nikhil
AU - Ohtake, Yasuyuki
AU - Saxena, Satya
AU - Anderson, Kenneth C
PY - 2003/11/1
Y1 - 2003/11/1
N2 - Smac, second mitochondria-derived activator of caspases, promotes apoptosis via activation of caspases. Heat shock protein 27 (Hsp27) negatively regulates another mitochondrial protein, cytochrome c, during apoptosis; however, the role of Hsp27 in modulating Smac release is unknown. Here we show that Hsp27 is overexpressed in both dexamethasone (Dex)-resistant multiple myeloma (MM) cell lines (MM.1R, U266, RPMI-8226) and primary patient cells. Blocking Hsp27 by an antisense (AS) strategy restores the apoptotic response to Dex in Dex-resistant MM cells by triggering the release of mitochondrial protein Smac, followed by activation of caspase-9 and caspase-3. Moreover, AS-Hsp27 overcomes interleukin-6 (IL-6)-mediated protection against Dex-induced apoptosis. These data demonstrate that Hsp27 inhibits the release of Smac, and thereby confers Dex resistance in MM cells.
AB - Smac, second mitochondria-derived activator of caspases, promotes apoptosis via activation of caspases. Heat shock protein 27 (Hsp27) negatively regulates another mitochondrial protein, cytochrome c, during apoptosis; however, the role of Hsp27 in modulating Smac release is unknown. Here we show that Hsp27 is overexpressed in both dexamethasone (Dex)-resistant multiple myeloma (MM) cell lines (MM.1R, U266, RPMI-8226) and primary patient cells. Blocking Hsp27 by an antisense (AS) strategy restores the apoptotic response to Dex in Dex-resistant MM cells by triggering the release of mitochondrial protein Smac, followed by activation of caspase-9 and caspase-3. Moreover, AS-Hsp27 overcomes interleukin-6 (IL-6)-mediated protection against Dex-induced apoptosis. These data demonstrate that Hsp27 inhibits the release of Smac, and thereby confers Dex resistance in MM cells.
KW - Apoptosis/drug effects
KW - Caspase 3
KW - Caspase 9
KW - Caspases/metabolism
KW - Cell Line, Tumor
KW - Dexamethasone/pharmacology
KW - Drug Resistance, Neoplasm
KW - HSP27 Heat-Shock Proteins
KW - Heat-Shock Proteins/physiology
KW - Humans
KW - Immunomagnetic Separation
KW - Interleukin-6/pharmacology
KW - Molecular Chaperones
KW - Multiple Myeloma/metabolism
KW - Neoplasm Proteins/physiology
KW - Oligonucleotides, Antisense/pharmacology
KW - Tumor Cells, Cultured
UR - http://www.scopus.com/inward/record.url?scp=0142245588&partnerID=8YFLogxK
U2 - 10.1182/blood-2003-05-1417
DO - 10.1182/blood-2003-05-1417
M3 - Journal article
C2 - 12855565
SN - 0006-4971
VL - 102
SP - 3379
EP - 3386
JO - Blood
JF - Blood
IS - 9
ER -