title: Extensive immunoglobulin production sensitizes myeloma cells for proteasome inhibition.
abstract: Multiple myeloma is an incurable plasma cell neoplasia characterized by the production of large amounts of monoclonal immunoglobulins. The proteasome inhibitor bortezomib (PS-341, Velcade) induces apoptosis in various malignant cells and has been approved for treatment of refractory multiple myeloma. Inhibition of the antiapoptotic transcription factor nuclear factor-kappaB (NF-kappaB) apparently contributes to the antitumor effects of bortezomib; however, this mechanism cannot fully explain the exceptional sensitivity of myeloma cells. Extensive protein synthesis as in myeloma cells is inherently accompanied by unfolded proteins, including defective ribosomal products (DRiPs), which need to be degraded by the ubiquitin-proteasome system. Therefore, we hypothesized that the proapoptotic effect of bortezomib in multiple myeloma is mainly due to the accumulation of unfolded proteins in cells with high protein biosynthesis. Using the IgG-secreting human myeloma cell line JK-6L and murine muH-chain-transfected Ag8.H myeloma cells, apoptosis induction upon proteasome inhibition was clearly correlated with the amount of immunoglobulin production. Preferentially in immunoglobulin-high myeloma cells, bortezomib triggered activation of caspases and induction of proapoptotic CHOP, a component of the terminal unfolded protein response induced by endoplasmic reticulum (ER) stress. In immunoglobulin-high cells, bortezomib increased the levels of proapoptotic Bax while reducing antiapoptotic Bcl-2. Finally, IgG-DRiPs were detected in proteasome inhibitor-treated cells. Hence, proteasome inhibitors induce apoptosis preferentially in cells with high synthesis rate of immunoglobulin associated with accumulation of unfolded proteins/DRiPs inducing ER stress. These findings further elucidate the antitumor activities of proteasome inhibitors and have important implications for optimizing clinical applications.
authors.affiliation: IZKF Research Group 2, Nikolaus-Fiebiger-Center of Molecular Medicine, University Hospital Erlangen, Glückstrasse 6, 91054 Erlangen, Germany.
authors.forename: Silke
authors.initials: S
authors.lastname: Meister
authors.forename: Ulrich
authors.initials: U
authors.lastname: Schubert
authors.forename: Kirsten
authors.initials: K
authors.lastname: Neubert
authors.forename: Kai
authors.initials: K
authors.lastname: Herrmann
authors.forename: Renate
authors.initials: R
authors.lastname: Burger
authors.forename: Martin
authors.initials: M
authors.lastname: Gramatzki
authors.forename: Sabine
authors.initials: S
authors.lastname: Hahn
authors.forename: Sandra
authors.initials: S
authors.lastname: Schreiber
authors.forename: Sabine
authors.initials: S
authors.lastname: Wilhelm
authors.forename: Martin
authors.initials: M
authors.lastname: Herrmann
authors.forename: Hans-Martin
authors.initials: HM
authors.lastname: Jäck
authors.forename: Reinhard E
authors.initials: RE
authors.lastname: Voll
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D045744:Cell Line, Tumor; D006801:Humans; D007074:Immunoglobulin G / Q000096:biosynthesis*; D007148:Immunoglobulin mu-Chains / Q000096:biosynthesis; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000201:enzymology / Q000276:immunology*; D016328:NF-kappa B / Q000378:metabolism; D011480:Protease Inhibitors / Q000494:pharmacology*; D061988:Proteasome Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011719:Pyrazines / Q000494:pharmacology; D018808:Transcription Factor AP-1 / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: C494826:BAX protein, human; D001897:Boronic Acids; D007074:Immunoglobulin G; D007148:Immunoglobulin mu-Chains; D016328:NF-kappa B; D011480:Protease Inhibitors; D061988:Proteasome Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D011719:Pyrazines; D018808:Transcription Factor AP-1; D051028:bcl-2-Associated X Protein; D000069286:Bortezomib