title: Myc regulates aggresome formation, the induction of Noxa, and apoptosis in response to the combination of bortezomib and SAHA.
abstract: The histone deacetylase inhibitor SAHA enhances cell death stimulated by the proteasome inhibitor bortezomib (BZ) by disrupting BZ-induced aggresome formation. Here we report that Myc regulates the sensitivity of multiple myeloma (MM) cells to BZ + SAHA-induced cell death. In MM cells, Myc expression directly correlated with intracellular ER content, protein synthesis rates, the percentage of aggresome-positive cells, and the sensitivity to BZ + SAHA-induced cell death. Accordingly, Myc knockdown markedly reduced the sensitivity of MM cells to BZ + SAHA-mediated apoptosis. Furthermore, activation of Myc was sufficient to provoke aggresome formation and thus sensitivity to BZ + SAHA, and these responses required de novo protein synthesis. BZ + SAHA-mediated stimulation of apoptosis includes the induction of the proapoptotic BH3-only protein Noxa as well as endoplasmic reticular stress, a disruption of calcium homeostasis, and activation of capase-4. Finally, knockdown studies demonstrated that both caspase-4 and Noxa play significant roles in Myc-driven sensitivity to BZ + SAHA-induced apoptosis. Collectively, our results establish a mechanistic link between Myc activity, regulation of protein synthesis, increases in HDAC6 expression and aggresome formation, induction of Noxa, and sensitivity to BZ + SAHA-induced apoptosis. These data suggest that MM patients with elevated Myc activity may be particularly sensitive to the BZ + SAHA combination.
authors.affiliation: The Institute for Drug Development, Cancer Therapy and Research Center at The University of Texas Health Science Center at San Antonio, USA. nawrocki@uthscsa.edu
authors.forename: Steffan T
authors.initials: ST
authors.lastname: Nawrocki
authors.forename: Jennifer S
authors.initials: JS
authors.lastname: Carew
authors.forename: Kirsteen H
authors.initials: KH
authors.lastname: Maclean
authors.forename: James F
authors.initials: JF
authors.lastname: Courage
authors.forename: Peng
authors.initials: P
authors.lastname: Huang
authors.forename: Janet A
authors.initials: JA
authors.lastname: Houghton
authors.forename: John L
authors.initials: JL
authors.lastname: Cleveland
authors.forename: Francis J
authors.initials: FJ
authors.lastname: Giles
authors.forename: David J
authors.initials: DJ
authors.lastname: McConkey
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D045744:Cell Line, Tumor; D022003:Cell Nucleus Structures / Q000187:drug effects* / Q000378:metabolism* / Q000648:ultrastructure; D003513:Cycloheximide / Q000494:pharmacology; D004171:Diploidy; D004357:Drug Synergism; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D005347:Fibroblasts / Q000187:drug effects / Q000473:pathology; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D009101:Multiple Myeloma / Q000473:pathology; D014176:Protein Biosynthesis / Q000187:drug effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D011719:Pyrazines / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000378:metabolism; D000077337:Vorinostat
chemical_list: D001897:Boronic Acids; D006877:Hydroxamic Acids; C498702:PMAIP1 protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; D016271:Proto-Oncogene Proteins c-myc; D011719:Pyrazines; D034741:RNA, Small Interfering; D000077337:Vorinostat; D000069286:Bortezomib; D003513:Cycloheximide; C433811:HDAC6 protein, human; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases