Show simple item record Xie B Nagalingam A Kuppusamy P Muniraj N Langford P Győrffy, Balázs Saxena NK Sharma D 2017-07-04T08:19:39Z 2017-07-04T08:19:39Z 2017
dc.identifier.citation pagination=40070, pages: 14; journalVolume=7; journalTitle=SCIENTIFIC REPORTS;
dc.identifier.uri doi:10.1038/srep40070
dc.description.abstract 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.
dc.relation.ispartof urn:issn:2045-2322
dc.title Benzyl Isothiocyanate potentiates p53 signaling and antitumor effects against breast cancer through activation of p53-LKB1 and p73-LKB1 axes
dc.type Journal Article 2017-03-13T09:53:35Z
dc.language.rfc3066 en
dc.identifier.mtmt 3172578
dc.identifier.pubmed 28071670
dc.contributor.department SE/AOK/K/II. Sz. Gyermekgyógyászati Klinika
dc.contributor.institution Semmelweis Egyetem
dc.mtmt.swordnote FELTÖLTŐ: Sonnevend Kinga - PMC PMC5223184

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