title: Benzyl Isothiocyanate potentiates p53 signaling and antitumor effects against breast cancer through activation of p53-LKB1 and p73-LKB1 axes.
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.
authors.affiliation: Department of Oncology, Johns Hopkins University School of Medicine and the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore MD 21231, USA.
authors.forename: Bei
authors.initials: B
authors.lastname: Xie
authors.affiliation: Department of Oncology, Johns Hopkins University School of Medicine and the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore MD 21231, USA.
authors.forename: Arumugam
authors.initials: A
authors.lastname: Nagalingam
authors.affiliation: Department of Medicine, University of Maryland School of Medicine, Baltimore MD 21201, USA.
authors.forename: Panjamurthy
authors.initials: P
authors.lastname: Kuppusamy
authors.affiliation: Department of Oncology, Johns Hopkins University School of Medicine and the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore MD 21231, USA.
authors.forename: Nethaji
authors.initials: N
authors.lastname: Muniraj
authors.affiliation: Department of Oncology, Johns Hopkins University School of Medicine and the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore MD 21231, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Langford
authors.affiliation: MTA TTK Momentum Cancer Biomarker Research Group, H-1117 Budapest, Semmelweis University, 2nd Dept. of Pediatrics, H-1094 Budapest, Hungary.
authors.forename: Balázs
authors.initials: B
authors.lastname: Győrffy
authors.affiliation: Department of Medicine, University of Maryland School of Medicine, Baltimore MD 21201, USA.
authors.forename: Neeraj K
authors.initials: NK
authors.lastname: Saxena
authors.affiliation: Department of Oncology, Johns Hopkins University School of Medicine and the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore MD 21231, USA.
authors.forename: Dipali
authors.initials: D
authors.lastname: Sharma
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D000970:Antineoplastic Agents / Q000378:metabolism*; D001943:Breast Neoplasms / Q000473:pathology*; D045744:Cell Line, Tumor; D006801:Humans; D017879:Isothiocyanates / Q000378:metabolism*; D010750:Phosphoproteins / Q000032:analysis; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D020543:Proteome / Q000032:analysis; D015398:Signal Transduction / Q000187:drug effects*; D000072160:Tumor Protein p73 / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D017879:Isothiocyanates; D010750:Phosphoproteins; D020543:Proteome; C495901:TP53 protein, human; C000606460:TP73 protein, human; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53; C031403:benzyl isothiocyanate; D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; D000091162:AMP-Activated Protein Kinase Kinases