title: Mitochondrial thioredoxin reductase regulates major cytotoxicity pathways of proteasome inhibitors in multiple myeloma cells.
abstract: It is generally accepted that intracellular oxidative stress induced by proteasome inhibitors is a byproduct of endoplasmic reticulum (ER) stress. Here we report a mechanism underlying the ability of proteasome inhibitors bortezomib (BTZ) and carfilzomib (CFZ) to directly induce oxidative and ER stresses in multiple myeloma (MM) cells via transcriptional repression of a gene encoding mitochondrial thioredoxin reductase (TXNRD2). TXNRD2 is critical for maintenance of intracellular red-ox status and detoxification of reactive oxygen species. Depletion of TXNRD2 to the levels detected in BTZ- or CFZ-treated cells causes oxidative stress, ER stress and death similar to those induced by proteasome inhibitors. Reciprocally, restoration of near-wildtype TXNRD2 amounts in MM cells treated with proteasome inhibitors reduces oxidative stress, ER stress and cell death by ~46%, ~35% and ~50%, respectively, compared with cells with unrestored TXNRD2 levels. Moreover, cells from three MM cell lines selected for resistance to BTZ demonstrate elevated levels of TXNRD2, indirectly confirming its functional role in BTZ resistance. Accordingly, ectopic expression of TXNRD2 in MM cell xenografts in immunocompromised mice blunts therapeutic effects of BTZ. Our data identify TXNRD2 as a potentially clinically relevant target, inhibition of which is critical for proteasome inhibitor-dependent cytotoxicity, oxidative stress and ER stress.
authors.affiliation: Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: E E
authors.initials: EE
authors.lastname: Fink
authors.affiliation: Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: S
authors.initials: S
authors.lastname: Mannava
authors.affiliation: Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: A
authors.initials: A
authors.lastname: Bagati
authors.affiliation: Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: A
authors.initials: A
authors.lastname: Bianchi-Smiraglia
authors.affiliation: Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: J R
authors.initials: JR
authors.lastname: Nair
authors.affiliation: Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: K
authors.initials: K
authors.lastname: Moparthy
authors.affiliation: Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: B C
authors.initials: BC
authors.lastname: Lipchick
authors.affiliation: National Research Center for Hematology, Moscow, Russia Federation.
authors.forename: M
authors.initials: M
authors.lastname: Drokov
authors.affiliation: Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: A
authors.initials: A
authors.lastname: Utley
authors.affiliation: Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: J
authors.initials: J
authors.lastname: Ross
authors.affiliation: National Research Center for Hematology, Moscow, Russia Federation.
authors.forename: L P
authors.initials: LP
authors.lastname: Mendeleeva
authors.affiliation: National Research Center for Hematology, Moscow, Russia Federation.
authors.forename: V G
authors.initials: VG
authors.lastname: Savchenko
authors.affiliation: Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: K P
authors.initials: KP
authors.lastname: Lee
authors.affiliation: Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: M A
authors.initials: MA
authors.lastname: Nikiforov
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D000069286:Bortezomib / Q000494:pharmacology; D045744:Cell Line, Tumor; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D005260:Female; D006801:Humans; D051379:Mice; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D018384:Oxidative Stress; D061988:Proteasome Inhibitors / Q000627:therapeutic use*; D017382:Reactive Oxygen Species / Q000378:metabolism; D054482:Thioredoxin Reductase 2 / Q000502:physiology*
chemical_list: D061988:Proteasome Inhibitors; D017382:Reactive Oxygen Species; D000069286:Bortezomib; C516127:TXNRD2 protein, human; D054482:Thioredoxin Reductase 2