SEARCH:   Advanced

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. This Article Full Text Full Text (PDF) Supplemental Figures All Versions of this Article: blood-2007-12-130823v1 112/7/2917    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Nawrocki, S. T. Articles by McConkey, D. J. Search for Related Content PubMed PubMed Citation Articles by Nawrocki, S. T. Articles by McConkey, D. J. Related Collections Neoplasia Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA Myc regulates aggresome formation, the induction of Noxa, and apoptosis in response to the combination of bortezomib and SAHA Steffan T. Nawrocki1,*, Jennifer S. Carew1,*, Kirsteen H. Maclean2, James F. Courage1, Peng Huang3, Janet A. Houghton4, John L. Cleveland5, Francis J. Giles1, and David J. McConkey6 1 The Institute for Drug Development, Cancer Therapy and Research Center at The University of Texas Health Science Center at San Antonio; 2 Department of Oncology, St Jude Children's Research Hospital, Memphis, TN; 3 Department of Molecular Pathology, The University of Texas M. D. Anderson Cancer Center, Houston; 4 Department of Cancer Biology, Lerner Research Institute, The Cleveland Clinic Foundation, OH; 5 Department of Cancer Biology, The Scripps Research Institute-Florida, Jupiter; and 6 Department of Urology, The University of Texas M. D. Anderson Cancer Center, Houston 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. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: E. White and R. S. DiPaola The Double-Edged Sword of Autophagy Modulation in Cancer Clin. Cancer Res., September 1, 2009; 15(17): 5308 - 5316. [Abstract] [Full Text] [PDF] A. Badros, A. M. Burger, S. Philip, R. Niesvizky, S. S. Kolla, O. Goloubeva, C. Harris, J. Zwiebel, J. J. Wright, I. Espinoza-Delgado, et al. Phase I Study of Vorinostat in Combination with Bortezomib for Relapsed and Refractory Multiple Myeloma Clin. Cancer Res., August 15, 2009; 15(16): 5250 - 5257. [Abstract] [Full Text] [PDF] D. J. McConkey Bortezomib paradigm shift in myeloma Blood, July 30, 2009; 114(5): 931 - 932. [Abstract] [Full Text] [PDF]

	Copyright © 2008 by American Society of Hematology         Online ISSN: 1528-0020