TY - JOUR
T1 - A small-molecule p53 activato induces apoptosis through inhibiting MDMX expression in breast cancer cells1,2
AU - Wang, Hongbo
AU - Yan, Chunhong
N1 - Funding Information:
Abbreviations: PARP, poly (ADP-ribose)polymerase; pol II, RNA polymerase II; qRT-PCR, quantitative reverse transcription–polymerase chain reaction; shRNA, short hairpin RNA; TUNEL, terminal deoxynucleotidyl transferase dUTP nick end labeling Address all correspondence to: Chunhong Yan, PhD, Albany Medical College, MC 165, 47 New Scotland Ave, Albany, NY 12208. E-mail: YanC@mail.amc.edu 1This work was supported in part by a National Institutes of Health grant R01CA139107 and a Department of Defense grant PC061106 (W81XWH-07-1-0095) to C.Y. The authors thank Hua Lu, Jiandong Chen, and Guillermina Lozano for providing reagents and comments. The authors declare no potential conflict of interest. 2This article refers to supplementary materials, which are designated by Figures W1 and W2 and are available online at www.neoplasia.com. Received 23 March 2011; Revised 2 May 2011; Accepted 4 May 2011 Copyright © 2011 Neoplasia Press, Inc. All rights reserved 1522-8002/11/$25.00 DOI 10.1593/neo.11438
PY - 2011/7
Y1 - 2011/7
N2 - The tumor suppressor p53 is often inactivated in breast cancer cells because the overexpression of its repressors (e.g., MDM2 and MDMX). Restoration of p53 activity by small molecules through counteracting p53 repressors can lead to in vivo tumor regression and is therefore considered a promising strategy for treatments of cancer. Recent efforts in high-throughput drug screening and rational drug design have identified several structurally diverse smallmolecule p53 activators, including a pseudourea derivative XI-011 (NSC146109). This small molecule strongly activates p53 while selectively inhibiting growth of transformed cells without inducing genotoxicity, indicating its potential as a drug lead for p53-targeted therapy. However, the mechanism(s) by which XI-011 activates p53 and the effects of XI-011 on growth of breast cancer cells are currently unknown. Here, we report that XI-011 promoted breast cancer cells to undergo apoptosis through activating p53 and inducing expression of proapoptotic genes. Importantly, we found that activation of p53 by this small moleculewas achieved through a novelmechanism, that is, inhibition ofMDMX expression. XI-011 repressed the MDMX promoter, resulting in down-regulation of MDMX messenger RNA level in MCF-7 cells. In line with these results, XI-011 decreased the viability of breast cancer cells expressing low levels of MDMX in a less-efficient manner. Interestingly, XI-011 acted additively with the MDM2 antagonist Nutlin-3a to inhibit growth of breast cancer cells. We conclude that XI-011 belongs to a novel class of small-molecule p53 activators that target MDMX and could be of value in treating breast cancer.
AB - The tumor suppressor p53 is often inactivated in breast cancer cells because the overexpression of its repressors (e.g., MDM2 and MDMX). Restoration of p53 activity by small molecules through counteracting p53 repressors can lead to in vivo tumor regression and is therefore considered a promising strategy for treatments of cancer. Recent efforts in high-throughput drug screening and rational drug design have identified several structurally diverse smallmolecule p53 activators, including a pseudourea derivative XI-011 (NSC146109). This small molecule strongly activates p53 while selectively inhibiting growth of transformed cells without inducing genotoxicity, indicating its potential as a drug lead for p53-targeted therapy. However, the mechanism(s) by which XI-011 activates p53 and the effects of XI-011 on growth of breast cancer cells are currently unknown. Here, we report that XI-011 promoted breast cancer cells to undergo apoptosis through activating p53 and inducing expression of proapoptotic genes. Importantly, we found that activation of p53 by this small moleculewas achieved through a novelmechanism, that is, inhibition ofMDMX expression. XI-011 repressed the MDMX promoter, resulting in down-regulation of MDMX messenger RNA level in MCF-7 cells. In line with these results, XI-011 decreased the viability of breast cancer cells expressing low levels of MDMX in a less-efficient manner. Interestingly, XI-011 acted additively with the MDM2 antagonist Nutlin-3a to inhibit growth of breast cancer cells. We conclude that XI-011 belongs to a novel class of small-molecule p53 activators that target MDMX and could be of value in treating breast cancer.
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U2 - 10.1593/neo.11438
DO - 10.1593/neo.11438
M3 - Article
C2 - 21750655
AN - SCOPUS:79960062837
SN - 1522-8002
VL - 13
SP - 611
EP - 619
JO - Neoplasia
JF - Neoplasia
IS - 7
ER -