title: Blockade of Hsp27 overcomes Bortezomib/proteasome inhibitor PS-341 resistance in lymphoma cells.
abstract: Bortezomib (PS-341), a selective inhibitor of proteasome, induces apoptosis in various tumor cells, but its mechanism of action is unclear. Treatment with PS-341 induces apoptosis in SUDHL6 (DHL6), but not SUDHL4 (DHL4), lymphoma cells. Microarray analysis shows high RNA levels of heat shock protein-27 (Hsp27) in DHL4 versus DHL6 cells, which correlates with Hsp27 protein expression. Blocking Hsp27 using an antisense strategy restores the apoptotic response to PS-341 in DHL4 cells; conversely, ectopic expression of wild-type Hsp27 renders PS-341-sensitive DHL6 cells resistant to PS-341. These findings provide the first evidence that Hsp27 confers PS-341 resistance.
authors.affiliation: The Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Dharminder
authors.initials: D
authors.lastname: Chauhan
authors.forename: Guilan
authors.initials: G
authors.lastname: Li
authors.forename: Reshma
authors.initials: R
authors.lastname: Shringarpure
authors.forename: Klaus
authors.initials: K
authors.lastname: Podar
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Ohtake
authors.forename: Teru
authors.initials: T
authors.lastname: Hideshima
authors.forename: Kenneth C
authors.initials: KC
authors.lastname: Anderson
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003546:Cysteine Endopeptidases; D019008:Drug Resistance, Neoplasm; D055551:HSP27 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D006801:Humans; D007976:Leupeptins / Q000494:pharmacology; D008223:Lymphoma / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D018832:Molecular Chaperones; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D046988:Proteasome Endopeptidase Complex; D011719:Pyrazines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014162:Transfection
chemical_list: D001897:Boronic Acids; D055551:HSP27 Heat-Shock Proteins; C057725:HSPB1 protein, human; D006360:Heat-Shock Proteins; D007976:Leupeptins; D018832:Molecular Chaperones; D009097:Multienzyme Complexes; D009363:Neoplasm Proteins; D011719:Pyrazines; D012333:RNA, Messenger; D000069286:Bortezomib; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde