Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Subscribe

Logo for

PNAS 104 (49): 19488-19493

Copyright © 2007 by the National Academy of Sciences.


BIOLOGICAL SCIENCES / MEDICAL SCIENCES

Tumor cell-selective regulation of NOXA by c-MYC in response to proteasome inhibition

Mikhail A. Nikiforov*,{dagger}, MaryBeth Riblett*,{dagger}, Wen-Hua Tang*,{dagger}, Vladimir Gratchouck*,{dagger}, Dazhong Zhuang*,{dagger}, Yolanda Fernandez*,{dagger},{ddagger}, Monique Verhaegen*,{dagger}, Sooryanarayana Varambally{dagger},§, Arul M. Chinnaiyan{dagger},§, Andrzej J. Jakubowiak§, and Maria S. Soengas*,{dagger},||

Departments of *Dermatology and Internal Medicine, {dagger}Comprehensive Cancer Center, and §Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109

Edited by Tak Wah Mak, University of Toronto, Toronto, ON, Canada, and approved October 3, 2007

Received for publication September 5, 2007.

Abstract: The proteasome controls a plethora of survival factors in all mammalian cells analyzed to date. Therefore, it is puzzling that proteasome inhibitors such as bortezomib can display a preferential toxicity toward malignant cells. In fact, proteasome inhibitors have the salient feature of promoting a dramatic induction of the proapoptotic protein NOXA in a tumor cell-restricted manner. However, the molecular determinants that control this specific regulation of NOXA are unknown. Here, we show that the induction of NOXA by bortezomib is directly dependent on the oncogene c-MYC. This requirement for c-MYC was found in a variety of tumor cell types, in marked contrast with dispensable roles of p53, HIF-1{alpha}, and E2F-1 (classical proteasomal targets that can regulate NOXA mRNA under stress). Conserved MYC-binding sites identified at the NOXA promoter were validated by ChIP and reporter assays. Down-regulation of the endogenous levels of c-MYC abrogated the induction of NOXA in proteasome-defective tumor cells. Conversely, forced expression of c-MYC enabled normal cells to accumulate NOXA and subsequently activate cell death programs in response to proteasome blockage. c-MYC is itself a proteasomal target whose levels or function are invariably up-regulated during tumor progression. Our data provide an unexpected function of c-MYC in the control of the apoptotic machinery, and reveal a long sought-after oncogenic event conferring sensitivity to proteasome inhibition.

Key Words: drug selectivity • melanoma • oncogenes • apoptosis • Bcl-2 family


Author contributions: M.A.N. and M.S.S. designed research; M.A.N., M.R., W.-H.T., V.G., D.Z., Y.F., M.V., and M.S.S. performed research; M.A.N., D.Z., S.V., A.M.C., and A.J.J. contributed new reagents/analytic tools; M.A.N. and M.S.S. analyzed data; and M.S.S. wrote the paper.

{ddagger}Present address: Merck KGaA, Bioresearch Laboratory, Parc Científic de Barcelona, 08028 Barcelona, Spain.

The authors declare no conflict of interest.

This article is a PNAS Direct Submission.

This article contains supporting information online at www.pnas.org/cgi/content/full/0708380104/DC1.

||To whom correspondence should be addressed at: University of Michigan Comprehensive Cancer Center (4217 CCGC), 1500 East Medical Center Drive, Ann Arbor, MI 48109. E-mail: soengas{at}umich.edu

© 2007 by The National Academy of Sciences of the USA


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
MYC Degradation under Low O2 Tension Promotes Survival by Evading Hypoxia-Induced Cell Death.
W. J. Wong, B. Qiu, M. S. Nakazawa, G. Qing, and M. C. Simon (2013)
Mol. Cell. Biol. 33, 3494-3504
   Abstract »    Full Text »    PDF »
Mammalian Target of Rapamycin Complex 1 (mTORC1) Enhances Bortezomib-induced Death in Tuberous Sclerosis Complex (TSC)-null Cells by a c-MYC-dependent Induction of the Unfolded Protein Response.
J. T. Babcock, H. B. Nguyen, Y. He, J. W. Hendricks, R. C. Wek, and L. A. Quilliam (2013)
J. Biol. Chem. 288, 15687-15698
   Abstract »    Full Text »    PDF »
SNF5 Reexpression in Malignant Rhabdoid Tumors Regulates Transcription of Target Genes by Recruitment of SWI/SNF Complexes and RNAPII to the Transcription Start Site of Their Promoters.
Y. Kuwahara, D. Wei, J. Durand, and B. E. Weissman (2013)
Mol. Cancer Res. 11, 251-260
   Abstract »    Full Text »    PDF »
KLF9 is a novel transcriptional regulator of bortezomib- and LBH589-induced apoptosis in multiple myeloma cells.
S. Mannava, D. Zhuang, J. R. Nair, R. Bansal, J. A. Wawrzyniak, S. N. Zucker, E. E. Fink, K. C. Moparthy, Q. Hu, S. Liu, et al. (2012)
Blood 119, 1450-1458
   Abstract »    Full Text »    PDF »
Pim Kinase Inhibitors Sensitize Prostate Cancer Cells to Apoptosis Triggered by Bcl-2 Family Inhibitor ABT-737.
J. H. Song and A. S. Kraft (2012)
Cancer Res. 72, 294-303
   Abstract »    Full Text »    PDF »
Multiple BH3 Mimetics Antagonize Antiapoptotic MCL1 Protein by Inducing the Endoplasmic Reticulum Stress Response and Up-regulating BH3-only Protein NOXA.
T. C. Albershardt, B. L. Salerni, R. S. Soderquist, D. J. P. Bates, A. A. Pletnev, A. F. Kisselev, and A. Eastman (2011)
J. Biol. Chem. 286, 24882-24895
   Abstract »    Full Text »    PDF »
AICAR induces apoptosis independently of AMPK and p53 through up-regulation of the BH3-only proteins BIM and NOXA in chronic lymphocytic leukemia cells.
A. F. Santidrian, D. M. Gonzalez-Girones, D. Iglesias-Serret, L. Coll-Mulet, A. M. Cosialls, M. de Frias, C. Campas, E. Gonzalez-Barca, E. Alonso, V. Labi, et al. (2010)
Blood 116, 3023-3032
   Abstract »    Full Text »    PDF »
Genome-Wide siRNA Screen for Modulators of Cell Death Induced by Proteasome Inhibitor Bortezomib.
S. Chen, J. L. Blank, T. Peters, X. J. Liu, D. M. Rappoli, M. D. Pickard, S. Menon, J. Yu, D. L. Driscoll, T. Lingaraj, et al. (2010)
Cancer Res. 70, 4318-4326
   Abstract »    Full Text »    PDF »
Regulation of Endoplasmic Reticulum Stress-induced Cell Death by ATF4 in Neuroectodermal Tumor Cells.
J. L. Armstrong, R. Flockhart, G. J. Veal, P. E. Lovat, and C. P. F. Redfern (2010)
J. Biol. Chem. 285, 6091-6100
   Abstract »    Full Text »    PDF »
Validation of SAG/RBX2/ROC2 E3 Ubiquitin Ligase as an Anticancer and Radiosensitizing Target.
L. Jia, J. Yang, X. Hao, M. Zheng, H. He, X. Xiong, L. Xu, and Y. Sun (2010)
Clin. Cancer Res. 16, 814-824
   Abstract »    Full Text »    PDF »
A Phase I Trial of Bortezomib with Temozolomide in Patients with Advanced Melanoma: Toxicities, Antitumor Effects, and Modulation of Therapeutic Targets.
Y. Su, K. I. Amiri, L. W. Horton, Y. Yu, G. D. Ayers, E. Koehler, M. C. Kelley, I. Puzanov, A. Richmond, and J. A. Sosman (2010)
Clin. Cancer Res. 16, 348-357
   Abstract »    Full Text »    PDF »
2-phenylacetylenesulfonamide (PAS) induces p53-independent apoptotic killing of B-chronic lymphocytic leukemia (CLL) cells.
A. J. Steele, A. G. Prentice, A. V. Hoffbrand, B. C. Yogashangary, S. M. Hart, M. W. Lowdell, E. R. Samuel, J. M. North, E. P. Nacheva, A. Chanalaris, et al. (2009)
Blood 114, 1217-1225
   Abstract »    Full Text »    PDF »
ERAD inhibitors integrate ER stress with an epigenetic mechanism to activate BH3-only protein NOXA in cancer cells.
Q. Wang, H. Mora-Jensen, M. A. Weniger, P. Perez-Galan, C. Wolford, T. Hai, D. Ron, W. Chen, W. Trenkle, A. Wiestner, et al. (2009)
PNAS 106, 2200-2205
   Abstract »    Full Text »    PDF »
Mapatumumab and lexatumumab induce apoptosis in TRAIL-R1 and TRAIL-R2 antibody-resistant NSCLC cell lines when treated in combination with bortezomib.
T. A. Luster, J. A. Carrell, K. McCormick, D. Sun, and R. Humphreys (2009)
Mol. Cancer Ther. 8, 292-302
   Abstract »    Full Text »    PDF »
Myc regulates aggresome formation, the induction of Noxa, and apoptosis in response to the combination of bortezomib and SAHA.
S. T. Nawrocki, J. S. Carew, K. H. Maclean, J. F. Courage, P. Huang, J. A. Houghton, J. L. Cleveland, F. J. Giles, and D. J. McConkey (2008)
Blood 112, 2917-2926
   Abstract »    Full Text »    PDF »
Newer Cytotoxic Agents: Attacking Cancer Broadly.
B. A. Teicher (2008)
Clin. Cancer Res. 14, 1610-1617
   Abstract »    Full Text »    PDF »

To Advertise     Find Products


Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882