title: The heat shock transcription factor 1 as a potential new therapeutic target in multiple myeloma.
abstract: The heat shock transcription factor 1 (HSF1) has recently been reported to promote malignant transformation and growth. Here we provide experimental evidence for a role of HSF1 in the pathogenesis of multiple myeloma (MM). Immunohistochemical analyses revealed that HSF1 was overexpressed in half of the investigated MM samples, including virtually all cases with extramedullary manifestations or anaplastic morphology. HSF1 function was inhibited either by siRNA-mediated knockdown or pharmacologically through treatment with triptolide. Both approaches caused depletion of HSF1, lowered the constitutively high expression of a multitude of protective HSPs (such as HSP90, HSP70, HSP40 and HSP27), induced apoptosis in human MM cells in vitro, and strongly reduced MM tumour growth in vivo. Furthermore, we observed that treatment-induced upregulation of HSPs after proteasome or HSP90 inhibition was critically dependent on HSF1. Importantly, the apoptotic effects of the HSP90 inhibitor NVP-AUY922 or the proteasome inhibitor bortezomib were strongly enhanced in combination with triptolide, suggesting a salvage role of HSF1-dependent HSP induction in response to drug treatment. Collectively, our data indicate that inhibition of HSF1 affects multiple protective HSPs and might therefore represent a therapeutic strategy - in particular in combination with proteasome or HSP90 inhibitors.
authors.affiliation: Department of Internal Medicine II, Comprehensive Cancer Centre Mainfranken, University Hospital of Würzburg, Würzburg, Germany.
authors.forename: Tanja
authors.initials: T
authors.lastname: Heimberger
authors.forename: Mindaugas
authors.initials: M
authors.lastname: Andrulis
authors.forename: Simone
authors.initials: S
authors.lastname: Riedel
authors.forename: Thorsten
authors.initials: T
authors.lastname: Stühmer
authors.forename: Heike
authors.initials: H
authors.lastname: Schraud
authors.forename: Andreas
authors.initials: A
authors.lastname: Beilhack
authors.forename: Thomas
authors.initials: T
authors.lastname: Bumm
authors.forename: Bjarne
authors.initials: B
authors.lastname: Bogen
authors.forename: Hermann
authors.initials: H
authors.lastname: Einsele
authors.forename: Ralf C
authors.initials: RC
authors.lastname: Bargou
authors.forename: Manik
authors.initials: M
authors.lastname: Chatterjee
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D004224:Diterpenes / Q000494:pharmacology; D015536:Down-Regulation; D004852:Epoxy Compounds / Q000494:pharmacology; D005260:Female; D055785:Gene Knockdown Techniques; D000076249:Heat Shock Transcription Factors; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D007555:Isoxazoles / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D009101:Multiple Myeloma / Q000188:drug therapy*; D009368:Neoplasm Transplantation; D010616:Phenanthrenes / Q000494:pharmacology; D010950:Plasma Cells / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects / Q000378:metabolism; D011719:Pyrazines / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000494:pharmacology; D012118:Resorcinols / Q000494:pharmacology; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000502:physiology*; D014183:Transplantation, Heterologous
chemical_list: C528044:5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-morpholin-4-ylmethylphenyl)isoxazole-3-carboxylic acid ethylamide; D000970:Antineoplastic Agents; D001897:Boronic Acids; D004268:DNA-Binding Proteins; D004224:Diterpenes; D004852:Epoxy Compounds; C000619706:HSF1 protein, human; D000076249:Heat Shock Transcription Factors; D006360:Heat-Shock Proteins; D007555:Isoxazoles; D010616:Phenanthrenes; D011719:Pyrazines; D034741:RNA, Small Interfering; D012118:Resorcinols; D014157:Transcription Factors; C001899:triptolide; D000069286:Bortezomib; D046988:Proteasome Endopeptidase Complex