title: Bortezomib-induced heat shock response protects multiple myeloma cells and is activated by heat shock factor 1 serine 326 phosphorylation.
abstract: Proteasome inhibitors such as bortezomib are highly active in multiple myeloma by affecting signaling cascades and leading to a toxic buildup of misfolded proteins. Bortezomib-treated cells activate the cytoprotective heat shock response (HSR), including upregulation of heat shock proteins (HSPs). Here we inhibited the bortezomib-induced HSR by silencing its master regulator, Heat Shock Factor 1 (HSF1). HSF1 silencing led to bortezomib sensitization. In contrast, silencing of individual and combination HSPs, except HSP40β, did not result in significant bortezomib sensitization. However, HSP40β did not entirely account for increased bortezomib sensitivity upon HSF1 silencing. To determine the mechanism of HSF1 activation, we assessed phosphorylation and observed bortezomib-inducible phosphorylation in cell lines and patient samples. We determined that this bortezomib-inducible event is phosphorylation at serine 326. Prior clinical use of HSP inhibitors in combination with bortezomib has been disappointing in multiple myeloma therapy. Our results provide a rationale for targeting HSF1 activation in combination with bortezomib to enhance multiple myeloma treatment efficacy.
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University and the Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: Shardule P
authors.initials: SP
authors.lastname: Shah
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University and the Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: Ajay K
authors.initials: AK
authors.lastname: Nooka
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University and the Emory University School of Medicine, Atlanta, GA, USA.|Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: David L
authors.initials: DL
authors.lastname: Jaye
authors.affiliation: Department of Medical Oncology and Hematology, Tom Baker Cancer Center, Calgary, AB, Canada.
authors.forename: Nizar J
authors.initials: NJ
authors.lastname: Bahlis
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University and the Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: Sagar
authors.initials: S
authors.lastname: Lonial
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University and the Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: Lawrence H
authors.initials: LH
authors.lastname: Boise
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology; D015153:Blotting, Western; D000069286:Bortezomib / Q000494:pharmacology*; D045744:Cell Line, Tumor; D000076249:Heat Shock Transcription Factors / Q000235:genetics / Q000378:metabolism*; D018869:Heat-Shock Response / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D008875:Middle Aged; D009101:Multiple Myeloma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D020011:Protective Agents / Q000494:pharmacology; D040901:Proteomics / Q000379:methods; D034622:RNA Interference; D012694:Serine / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; C000619706:HSF1 protein, human; D000076249:Heat Shock Transcription Factors; D020011:Protective Agents; D012694:Serine; D000069286:Bortezomib
keywords: HSF1; bortezomib; heat shock; myeloma