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Blood, 1 October 2008, Vol. 112, No. 7, pp. 2917-2926.
Prepublished online as a Blood First Edition Paper on July 18, 2008; DOI 10.1182/blood-2007-12-130823.
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Submitted December 28, 2007
Accepted June 22, 2008
Myc regulates aggresome formation, the induction of Noxa, and apoptosis in response to the combination of bortezomib and SAHA
Steffan T. Nawrocki*, Jennifer S. Carew, Kirsteen H. Maclean, James F. Courage, Peng Huang, Janet A. Houghton, John L. Cleveland, Francis J. Giles, and David J. McConkey
CTRC Institute for Drug Development, University of Texas Health Science Center at San Antonio, San Antonio, TX, United States
Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN, United States
Department of Molecular Pathology, University of Texas M.D. Anderson Cancer Center, Houston, TX, United States
Department of Cancer Biology, Cleveland Clinic Foundation, Cleveland, OH, United States
Department of Cancer Biology, The Scripps Research Institute-Florida, Jupiter, FL, United States
Department of Urology, University of Texas M.D. Anderson Cancer Center, Houston, TX, United States
* Corresponding author; email: nawrocki{at}uthscsa.edu.
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.
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