title: Hsp70 inhibition induces myeloma cell death via the intracellular accumulation of immunoglobulin and the generation of proteotoxic stress.
abstract: Multiple myeloma (MM) cells rely on protein homeostatic mechanisms for survival. These mechanisms could be therapeutically targeted via modulation of the heat shock response. We studied the roles of Hsp72 and Hsc70, and show that the two major cytoplasmic Hsp70s play a key role in regulating protein homeostasis and controlling multiple oncogenic pathways in MM, and their inhibition can lead to myeloma cell death. Our study provides further evidence that targeting Hsp70 represents a novel therapeutic approach which may be effective in the treatment of MM.
authors.affiliation: Haemato-Oncology Research Unit, Division of Molecular Pathology, Cancer Therapeutics and Clinical Studies, The Institute of Cancer Research, London SM2 5NG, UK.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.forename: Jacqueline J L
authors.initials: JJ
authors.lastname: Fok
authors.forename: Fabio
authors.initials: F
authors.lastname: Mirabella
authors.forename: Lauren I
authors.initials: LI
authors.lastname: Aronson
authors.forename: Rosemary A
authors.initials: RA
authors.lastname: Fryer
authors.forename: Paul
authors.initials: P
authors.lastname: Workman
authors.forename: Gareth J
authors.initials: GJ
authors.lastname: Morgan
authors.forename: Faith E
authors.initials: FE
authors.lastname: Davies
mesh_terms: D016923:Cell Death / Q000235:genetics; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics; D020868:Gene Silencing; D050883:HSC70 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D018840:HSP70 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007136:Immunoglobulins / Q000378:metabolism*; D042541:Intracellular Space / Q000378:metabolism; D009101:Multiple Myeloma / Q000235:genetics* / Q000378:metabolism*; D034622:RNA Interference; D013312:Stress, Physiological / Q000235:genetics; D025801:Ubiquitin / Q000378:metabolism
chemical_list: D050883:HSC70 Heat-Shock Proteins; D018840:HSP70 Heat-Shock Proteins; D007136:Immunoglobulins; D025801:Ubiquitin
keywords: ER stress; Haematology; Hsp70; Multiple myeloma; Protein folding