title: A Bim-targeting strategy overcomes adaptive bortezomib resistance in myeloma through a novel link between autophagy and apoptosis.
abstract: Bim contributes to resistance to various standard and novel agents. Here we demonstrate that Bim plays a functional role in bortezomib resistance in multiple myeloma (MM) cells and that targeting Bim by combining histone deacetylase inhibitors (HDACIs) with BH3 mimetics (eg, ABT-737) overcomes bortezomib resistance. BH3-only protein profiling revealed high Bim levels (Bim(hi)) in most MM cell lines and primary CD138(+) MM samples. Whereas short hairpin RNA Bim knockdown conferred bortezomib resistance in Bim(hi) cells, adaptive bortezomib-resistant cells displayed marked Bim downregulation. HDACI upregulated Bim and, when combined with ABT-737, which released Bim from Bcl-2/Bcl-xL, potently killed bortezomib-resistant cells. These events were correlated with Bim-associated autophagy attenuation, whereas Bim knockdown sharply increased autophagy in Bim(hi) cells. In Bim(low) cells, autophagy disruption by chloroquine (CQ) was required for HDACI/ABT-737 to induce Bim expression and lethality. CQ also further enhanced HDACI/ABT-737 lethality in bortezomib-resistant cells. Finally, HDACI failed to diminish autophagy or potentiate ABT-737-induced apoptosis in bim(-/-) mouse embryonic fibroblasts. Thus, Bim deficiency represents a novel mechanism of adaptive bortezomib resistance in MM cells, and Bim-targeting strategies combining HDACIs (which upregulate Bim) and BH3 mimetics (which unleash Bim from antiapoptotic proteins) overcomes such resistance, in part by disabling cytoprotective autophagy.
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Virginia Commonwealth University and the Massey Cancer Center, Richmond, VA;
authors.forename: Shuang
authors.initials: S
authors.lastname: Chen
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Virginia Commonwealth University and the Massey Cancer Center, Richmond, VA; National Engineering Laboratory for Druggable Gene and Protein Screening, Northeast Normal University, Changchun, China;
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Virginia Commonwealth University and the Massey Cancer Center, Richmond, VA;
authors.forename: Liang
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Virginia Commonwealth University and the Massey Cancer Center, Richmond, VA; Department of Hematology, Beijing Chaoyang Hospital of Capital Medical University, Beijing, China;
authors.forename: Yun
authors.initials: Y
authors.lastname: Leng
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Virginia Commonwealth University and the Massey Cancer Center, Richmond, VA;
authors.forename: Hui
authors.initials: H
authors.lastname: Lin
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Virginia Commonwealth University and the Massey Cancer Center, Richmond, VA;
authors.forename: Maciej
authors.initials: M
authors.lastname: Kmieciak
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Virginia Commonwealth University and the Massey Cancer Center, Richmond, VA;
authors.forename: Xin-Yan
authors.initials: XY
authors.lastname: Pei
authors.affiliation: Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX; and.
authors.forename: Richard
authors.initials: R
authors.lastname: Jones
authors.affiliation: Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX; and.
authors.forename: Robert Z
authors.initials: RZ
authors.lastname: Orlowski
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Virginia Commonwealth University and the Massey Cancer Center, Richmond, VA;
authors.forename: Yun
authors.identifier: http://orcid.org/0000-0003-2285-0818
authors.initials: Y
authors.lastname: Dai
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Virginia Commonwealth University and the Massey Cancer Center, Richmond, VA; Virginia Institute of Molecular Medicine, Virginia Commonwealth University, Richmond VA.
authors.forename: Steven
authors.initials: S
authors.lastname: Grant
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D001343:Autophagy / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D000072224:Bcl-2-Like Protein 11; D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005455:Fluorescent Antibody Technique; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage / Q000494:pharmacology; D015151:Immunoblotting; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D009101:Multiple Myeloma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011719:Pyrazines / Q000494:pharmacology; D034622:RNA Interference; D047368:Tumor Burden / Q000187:drug effects / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D001897:Boronic Acids; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D011719:Pyrazines; C528828:suberoyl bis-hydroxamic acid; D000069286:Bortezomib