Myc regulates aggresome formation, the induction of Noxa, and apoptosis in response to the combination of bortezomib and SAHA.
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.
Nawrocki
Steffan T
ST
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
Carew
Jennifer S
JS
Maclean
Kirsteen H
KH
Courage
James F
JF
Huang
Peng
P
Houghton
Janet A
JA
Cleveland
John L
JL
Giles
Francis J
FJ
McConkey
David J
DJ
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
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