HSP27 inhibits release of mitochondrial protein Smac in multiple myeloma cells and confers dexamethasone resistance

Authors:
Chauhan D, Li G, Hideshima T, Podar K, Mitsiades C, Midsiades N, Catley L, Tai YT, Hayashi T, Shringharpure R, Burger R, Munshi N, Ohtake Y, Saxena S and Anderson KC
In:
Blood (2003) 102(9): 3379-3386
Cells used in publication:
RPMI8226
Species: human
Tissue Origin: blood
U266
Species: human
Tissue Origin: blood
MM.1S
Species: human
Tissue Origin: blood
Experiment
Smac (second mitochondria-derived activator of caspases) promotes apoptosis via activation of caspases. Elevated levels of heat shock protein-27 (Hsp27) transcripts have been observed in dexamethasone (Dex)-resistant multiple myeloma (MM) cell lines. However, the fuctional significance of Hsp27 in MM cells remains undefined. The authors studied the role of Hsp27 in MM cell lines by nucleofecting MM.1R, MM.1S, U266, and RPMI-8226 MM cells with an expression vector containing antisense Hsp27 cDNA or with empty vector. The results demonstrated that antisense Hsp27 inhibits the release of Hsp27, and thereby confers Dex-restistance in MM cells.
Abstract
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.