Hsp27 inhibits release of mitochondrial protein Smac in multiple myeloma cells and confers dexamethasone resistance
- 1 November 2003
- journal article
- Published by American Society of Hematology in Blood
- Vol. 102 (9) , 3379-3386
- https://doi.org/10.1182/blood-2003-05-1417
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.Keywords
This publication has 49 references indexed in Scilit:
- Identification of genes regulated by 2-methoxyestradiol (2ME2) in multiple myeloma cells using oligonucleotide arraysBlood, 2003
- Moving disease biology from the lab to the clinicCancer, 2003
- Overexpression of the myeloma-associated oncogene fibroblast growth factor receptor 3 confers dexamethasone resistanceBlood, 2002
- Comparison of gene expression profiling between malignant and normal plasma cells with oligonucleotide arraysOncogene, 2002
- 2-Methoxyestradiol overcomes drug resistance in multiple myeloma cellsBlood, 2002
- Activation of NF-κB and upregulation of intracellular anti-apoptotic proteins via the IGF-1/Akt signaling in human multiple myeloma cells: therapeutic implicationsOncogene, 2002
- Identification of genes regulated by Dexamethasone in multiple myeloma cells using oligonucleotide arraysOncogene, 2002
- Bcl-2 overexpression is associated with resistance to dexamethasone, but not melphalan, in multiple myeloma cells.International Journal of Oncology, 1998
- A mechanism of resistance to glucocorticoids in multiple myeloma: transient expression of a truncated glucocorticoid receptor mRNABlood, 1992
- Prednisone pulse therapy for refractory myelomaBlood, 1983