title: Hsp27 inhibits release of mitochondrial protein Smac in multiple myeloma cells and confers dexamethasone resistance.
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.
authors.affiliation: Jerome Lipper Multiple Myeloma Center, Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Dharminder
authors.initials: D
authors.lastname: Chauhan
authors.forename: Guilan
authors.initials: G
authors.lastname: Li
authors.forename: Teru
authors.initials: T
authors.lastname: Hideshima
authors.forename: Klaus
authors.initials: K
authors.lastname: Podar
authors.forename: Constantine
authors.initials: C
authors.lastname: Mitsiades
authors.forename: Nicholas
authors.initials: N
authors.lastname: Mitsiades
authors.forename: Laurence
authors.initials: L
authors.lastname: Catley
authors.forename: Yu Tzu
authors.initials: YT
authors.lastname: Tai
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Hayashi
authors.forename: Reshma
authors.initials: R
authors.lastname: Shringarpure
authors.forename: Renate
authors.initials: R
authors.lastname: Burger
authors.forename: Nikhil
authors.initials: N
authors.lastname: Munshi
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Ohtake
authors.forename: Satya
authors.initials: S
authors.lastname: Saxena
authors.forename: Kenneth C
authors.initials: KC
authors.lastname: Anderson
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D003907:Dexamethasone / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D055551:HSP27 Heat-Shock Proteins; D006360:Heat-Shock Proteins / Q000502:physiology*; D006801:Humans; D018189:Immunomagnetic Separation; D015850:Interleukin-6 / Q000494:pharmacology; D018832:Molecular Chaperones; D009101:Multiple Myeloma / Q000378:metabolism / Q000473:pathology*; D009363:Neoplasm Proteins / Q000502:physiology; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D014407:Tumor Cells, Cultured
chemical_list: D055551:HSP27 Heat-Shock Proteins; C057725:HSPB1 protein, human; D006360:Heat-Shock Proteins; D015850:Interleukin-6; D018832:Molecular Chaperones; D009363:Neoplasm Proteins; D016376:Oligonucleotides, Antisense; D003907:Dexamethasone; C505407:CASP3 protein, human; C506433:CASP9 protein, human; D053148:Caspase 3; D053453:Caspase 9; D020169:Caspases