Show simple item record

dc.contributor.authorKovacevic, Zaklina
dc.contributor.authorMenezes, Sharleen V
dc.contributor.authorSahni, Sumit
dc.contributor.authorKalinowski, Danuta S
dc.contributor.authorBae, Dong-Hun
dc.contributor.authorLane, Darius JR
dc.contributor.authorRichardson, Des R
dc.date.accessioned2022-05-18T01:16:00Z
dc.date.available2022-05-18T01:16:00Z
dc.date.issued2016
dc.identifier.issn0021-9258en_US
dc.identifier.doi10.1074/jbc.M115.689653en_US
dc.identifier.urihttp://hdl.handle.net/10072/405467
dc.description.abstractN-MYC downstream-regulated gene-1 (NDRG1) is a potent growth and metastasis suppressor that acts through its inhibitory effects on a wide variety of cellular signaling pathways, including the TGF-β pathway, protein kinase B (AKT)/PI3K pathway, RAS, etc. To investigate the hypothesis that its multiple effects could be regulated by a common upstream effector, the role of NDRG1 on the epidermal growth factor receptor (EGFR) and other members of the ErbB family, namely human epidermal growth factor receptor 2 (HER2) and human epidermal growth factor receptor 3 (HER3), was examined. We demonstrate that NDRG1 markedly decreased the expression and activation of EGFR, HER2, and HER3 in response to the epidermal growth factor (EGF) ligand, while also inhibiting formation of the EGFR/HER2 and HER2/HER3 heterodimers. In addition, NDRG1also decreased activation of the downstream MAPKK in response to EGF. Moreover, novel anti-tumor agents of the di-2-pyridylketone class of thiosemicarbazones, namely di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone and di-2-pyridylketone 4-cyclohexyl-4-methyl-3-thiosemicarbazone, which markedly up-regulate NDRG1, were found to inhibit EGFR, HER2, and HER3 expression and phosphorylation in cancer cells. However, the mechanism involved appeared dependent on NDRG1 for di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone, but was independent of this metastasis suppressor for di-2-pyridylketone 4-cyclohexyl-4-methyl-3-thiosemicarbazone. This observation demonstrates that small structural changes in thiosemicarbazones result in marked alterations in molecular targeting. Collectively, these results reveal a mechanism for the extensive downstream effects on cellular signaling attributed to NDRG1. Furthermore, this study identifies a novel approach for the treatment of tumors resistant to traditional EGFR inhibitors.en_US
dc.description.peerreviewedYesen_US
dc.description.sponsorshipEffective Antiproliferative Agentsen_US
dc.languageEnglishen_US
dc.publisherAMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INCen_US
dc.relation.ispartofpagefrom1029en_US
dc.relation.ispartofpageto1052en_US
dc.relation.ispartofissue3en_US
dc.relation.ispartofjournalJournal of Biological Chemistryen_US
dc.relation.ispartofvolume291en_US
dc.subject.fieldofresearchChemical sciencesen_US
dc.subject.fieldofresearchBiological sciencesen_US
dc.subject.fieldofresearchBiomedical and clinical sciencesen_US
dc.subject.fieldofresearchcode34en_US
dc.subject.fieldofresearchcode31en_US
dc.subject.fieldofresearchcode32en_US
dc.subject.keywordsScience & Technologyen_US
dc.subject.keywordsLife Sciences & Biomedicineen_US
dc.subject.keywordsBiochemistry & Molecular Biologyen_US
dc.subject.keywordsEpidermal-Growth-Factoren_US
dc.titleThe Metastasis Suppressor, N-MYC Downstream-regulated Gene-1 (NDRG1), Down-regulates the ErbB Family of Receptors to Inhibit Downstream Oncogenic Signalling Pathwaysen_US
dc.typeJournal articleen_US
dc.type.descriptionC1 - Articlesen_US
dcterms.bibliographicCitationKovacevic, Z; Menezes, SV; Sahni, S; Kalinowski, DS; Bae, D-H; Lane, DJR; Richardson, DR, The Metastasis Suppressor, N-MYC Downstream-regulated Gene-1 (NDRG1), Down-regulates the ErbB Family of Receptors to Inhibit Downstream Oncogenic Signaling Pathways, Journal of Biological Chemistry, 2016, 291 (3), pp. 1029-1052en_US
dcterms.licensehttps://creativecommons.org/licenses/by/4.0/en_US
dc.date.updated2021-06-30T00:57:08Z
dc.description.versionVersion of Record (VoR)en_US
gro.rights.copyright© The Author(s) 2017. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.en_US
gro.hasfulltextFull Text
gro.griffith.authorRichardson, Des R.


Files in this item

This item appears in the following Collection(s)

  • Journal articles
    Contains articles published by Griffith authors in scholarly journals.

Show simple item record