Benzyl Isothiocyanate potentiates p53 signaling and antitumor effects against breast cancer through activation of p53-LKB1 and p73-LKB1 axes

doi:10.1038/srep40070

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	Benzyl Isothiocyanate potentiates p53 signaling and antitumor effects against breast cancer through activation of p53-LKB1 and p73-LKB1 axes
	Xie, B; Nagalingam, A; Kuppusamy, P; Muniraj, N; Langford, P; Gyorffy, B; Saxena, NK; Sharma, D; Sharma, D (reprint author), Johns Hopkins Univ, Sch Med, Dept Oncol, Baltimore, MD 21231 USA.; Sharma, D (reprint author), Johns Hopkins, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD 21231 USA.
刊名	SCIENTIFIC REPORTS
	2017-01-10
卷号	7
ISSN号	2045-2322
DOI	10.1038/srep40070
文献子类	Article
英文摘要	Functional reactivation of p53 pathway, although arduous, can potentially provide a broad-based strategy for cancer therapy owing to frequent p53 inactivation in human cancer. Using a phosphoprotein-screening array, we found that Benzyl Isothiocynate, (BITC) increases p53 phosphorylation in breast cancer cells and reveal an important role of ERK and PRAS40/MDM2 in BITC-mediated p53 activation. We show that BITC rescues and activates p53-signaling network and inhibits growth of p53-mutant cells. Mechanistically, BITC induces p73 expression in p53-mutant cells, disrupts the interaction of p73 and mutant-p53, thereby releasing p73 from sequestration and allowing it to be transcriptionally active. Furthermore, BITC-induced p53 and p73 axes converge on tumor-suppressor LKB1 which is transcriptionally upregulated by p53 and p73 in p53-wild-type and p53-mutant cells respectively; and in a feed-forward mechanism, LKB1 tethers with p53 and p73 to get recruited to p53-responsive promoters. Analyses of BITC-treated xenografts using LKB1-null cells corroborate in vitro mechanistic findings and establish LKB1 as the key node whereby BITC potentiates as well as rescues p53-pathway in p53-wild-type as well as p53-mutant cells. These data provide first in vitro and in vivo evidence of the integral role of previously unrecognized crosstalk between BITC, p53/LKB1 and p73/LKB1 axes in breast tumor growth-inhibition.
学科主题	Science & Technology - Other Topics
出版地	LONDON
资助项目	美国国立卫生研究院项目
项目编号	NCI NIH [1R21CA185943-01alpha1, R01CA131294, R21CA155686] ; OTKA [K108655] ; Avon Foundation ; Breast Cancer Research Foundation (BCRF) [90047965] ; Fetting Fund
语种	英语
WOS记录号	WOS:000391547200002
资助机构	NIH
内容类型	期刊论文
源URL	[http://ir.lzu.edu.cn/handle/262010/188744]
专题	基础医学院_期刊论文
通讯作者	Sharma, D (reprint author), Johns Hopkins Univ, Sch Med, Dept Oncol, Baltimore, MD 21231 USA.; Sharma, D (reprint author), Johns Hopkins, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD 21231 USA.; Saxena, NK (reprint author), Univ Maryland, Sch Med, Dept Med, Baltimore, MD 21201 USA.
推荐引用方式 GB/T 7714	Xie, B,Nagalingam, A,Kuppusamy, P,et al. Benzyl Isothiocyanate potentiates p53 signaling and antitumor effects against breast cancer through activation of p53-LKB1 and p73-LKB1 axes[J]. SCIENTIFIC REPORTS,2017,7.
APA	Xie, B.,Nagalingam, A.,Kuppusamy, P.,Muniraj, N.,Langford, P.,...&Saxena, NK .(2017).Benzyl Isothiocyanate potentiates p53 signaling and antitumor effects against breast cancer through activation of p53-LKB1 and p73-LKB1 axes.SCIENTIFIC REPORTS,7.
MLA	Xie, B,et al."Benzyl Isothiocyanate potentiates p53 signaling and antitumor effects against breast cancer through activation of p53-LKB1 and p73-LKB1 axes".SCIENTIFIC REPORTS 7(2017).