title: Novel Thiosemicarbazones Inhibit Lysine-Rich Carcinoembryonic Antigen-Related Cell Adhesion Molecule 1 (CEACAM1) Coisolated (LYRIC) and the LYRIC-Induced Epithelial-Mesenchymal Transition via Upregulation of N-Myc Downstream-Regulated Gene 1 (NDRG1).
abstract: Tumor necrosis factorα(TNFα) plays a vital role in cancer progression as it is associated with inflammation and promotion of cancer angiogenesis and metastasis. The effects of TNFαare mediated by its downstream target, the oncogene lysine-rich CEACAM1 coisolated protein (LYRIC, also known as metadherin or astrocyte elevated gene-1). LYRIC plays an important role in activating the nuclear factor-ĸB (NF-κB) signaling pathway, which controls multiple cellular processes, including proliferation, apoptosis, migration, etc. In contrast, the metastasis suppressor N-myc downstream regulated gene 1 (NDRG1) has the opposite effect on the NF-κB pathway, being able to inhibit NF-κB activation and reduce angiogenesis, proliferation, migration, and cancer cell invasion. These potent anticancer properties make NDRG1 an ideal therapeutic target. Indeed, a novel class of thiosemicarbazone anticancer agents that target this molecule has been developed; the lead agent, di-2-pyridylketone 4-cyclohexyl-4-methyl-3-thiosemicarbazone, has recently entered clinical trials for advanced and resistant cancers. To further elucidate the interaction between NDRG1 and oncogenic signaling, this study for the first time assessed the effects of NDRG1 on the tumorigenic properties of TNFαand its downstream target, LYRIC. We have demonstrated that NDRG1 inhibits the TNFα-mediated epithelial-to-mesenchymal transition. Further, NDRG1 also potently inhibited LYRIC expression, with a negative feedback loop existing between these two molecules. Examining the mechanism involved, we demonstrated that NDRG1 inhibited phosphatidylinositol 3-kinase/AKT signaling, leading to reduced levels of the LYRIC transcriptional activator, c-Myc. Finally, we demonstrated that novel thiosemicarbazones that upregulate NDRG1 also inhibit LYRIC expression, further highlighting their marked potential for cancer treatment.
authors.affiliation: Molecular Pharmacology and Pathology Program, Department of Pathology, University of Sydney, Sydney, New South Wales, Australia (R.X., I.H.Y.P., S.V.M., L.F., D.S.K., M.L.H.H., D.R.R., Z.K.); Department of Radiation Oncology, First Affiliated Hospital of Xi'an Jiaotong University, China (R.X., X.Z.); and Department of Applied Biology and Chemical Technology, the Hong Kong Polytechnic University, Hong Kong, China (I.H.Y.P.).
authors.forename: Ruxing
authors.initials: R
authors.lastname: Xi
authors.affiliation: Molecular Pharmacology and Pathology Program, Department of Pathology, University of Sydney, Sydney, New South Wales, Australia (R.X., I.H.Y.P., S.V.M., L.F., D.S.K., M.L.H.H., D.R.R., Z.K.); Department of Radiation Oncology, First Affiliated Hospital of Xi'an Jiaotong University, China (R.X., X.Z.); and Department of Applied Biology and Chemical Technology, the Hong Kong Polytechnic University, Hong Kong, China (I.H.Y.P.).
authors.forename: Ivan Ho Yuen
authors.initials: IH
authors.lastname: Pun
authors.affiliation: Molecular Pharmacology and Pathology Program, Department of Pathology, University of Sydney, Sydney, New South Wales, Australia (R.X., I.H.Y.P., S.V.M., L.F., D.S.K., M.L.H.H., D.R.R., Z.K.); Department of Radiation Oncology, First Affiliated Hospital of Xi'an Jiaotong University, China (R.X., X.Z.); and Department of Applied Biology and Chemical Technology, the Hong Kong Polytechnic University, Hong Kong, China (I.H.Y.P.).
authors.forename: Sharleen V
authors.initials: SV
authors.lastname: Menezes
authors.affiliation: Molecular Pharmacology and Pathology Program, Department of Pathology, University of Sydney, Sydney, New South Wales, Australia (R.X., I.H.Y.P., S.V.M., L.F., D.S.K., M.L.H.H., D.R.R., Z.K.); Department of Radiation Oncology, First Affiliated Hospital of Xi'an Jiaotong University, China (R.X., X.Z.); and Department of Applied Biology and Chemical Technology, the Hong Kong Polytechnic University, Hong Kong, China (I.H.Y.P.).
authors.forename: Leyla
authors.initials: L
authors.lastname: Fouani
authors.affiliation: Molecular Pharmacology and Pathology Program, Department of Pathology, University of Sydney, Sydney, New South Wales, Australia (R.X., I.H.Y.P., S.V.M., L.F., D.S.K., M.L.H.H., D.R.R., Z.K.); Department of Radiation Oncology, First Affiliated Hospital of Xi'an Jiaotong University, China (R.X., X.Z.); and Department of Applied Biology and Chemical Technology, the Hong Kong Polytechnic University, Hong Kong, China (I.H.Y.P.).
authors.forename: Danuta S
authors.initials: DS
authors.lastname: Kalinowski
authors.affiliation: Molecular Pharmacology and Pathology Program, Department of Pathology, University of Sydney, Sydney, New South Wales, Australia (R.X., I.H.Y.P., S.V.M., L.F., D.S.K., M.L.H.H., D.R.R., Z.K.); Department of Radiation Oncology, First Affiliated Hospital of Xi'an Jiaotong University, China (R.X., X.Z.); and Department of Applied Biology and Chemical Technology, the Hong Kong Polytechnic University, Hong Kong, China (I.H.Y.P.).
authors.forename: Michael L H
authors.initials: ML
authors.lastname: Huang
authors.affiliation: Molecular Pharmacology and Pathology Program, Department of Pathology, University of Sydney, Sydney, New South Wales, Australia (R.X., I.H.Y.P., S.V.M., L.F., D.S.K., M.L.H.H., D.R.R., Z.K.); Department of Radiation Oncology, First Affiliated Hospital of Xi'an Jiaotong University, China (R.X., X.Z.); and Department of Applied Biology and Chemical Technology, the Hong Kong Polytechnic University, Hong Kong, China (I.H.Y.P.).
authors.forename: Xiaozhi
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Molecular Pharmacology and Pathology Program, Department of Pathology, University of Sydney, Sydney, New South Wales, Australia (R.X., I.H.Y.P., S.V.M., L.F., D.S.K., M.L.H.H., D.R.R., Z.K.); Department of Radiation Oncology, First Affiliated Hospital of Xi'an Jiaotong University, China (R.X., X.Z.); and Department of Applied Biology and Chemical Technology, the Hong Kong Polytechnic University, Hong Kong, China (I.H.Y.P.) zaklina.kovacevic@sydney.edu.au d.richardson@med.usyd.edu.au.
authors.forename: Des R
authors.initials: DR
authors.lastname: Richardson
authors.affiliation: Molecular Pharmacology and Pathology Program, Department of Pathology, University of Sydney, Sydney, New South Wales, Australia (R.X., I.H.Y.P., S.V.M., L.F., D.S.K., M.L.H.H., D.R.R., Z.K.); Department of Radiation Oncology, First Affiliated Hospital of Xi'an Jiaotong University, China (R.X., X.Z.); and Department of Applied Biology and Chemical Technology, the Hong Kong Polytechnic University, Hong Kong, China (I.H.Y.P.) zaklina.kovacevic@sydney.edu.au d.richardson@med.usyd.edu.au.
authors.forename: Zaklina
authors.initials: Z
authors.lastname: Kovacevic
mesh_terms: D015815:Cell Adhesion Molecules / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D003676:Deferoxamine / Q000494:pharmacology; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D020868:Gene Silencing / Q000187:drug effects; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008565:Membrane Proteins; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D016601:RNA-Binding Proteins; D013882:Thiosemicarbazones / Q000737:chemistry / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects*; D014746:Vimentin / Q000378:metabolism; D000099259:N-myc Downstream-Regulated Gene 1 Protein
chemical_list: D015815:Cell Adhesion Molecules; D018797:Cell Cycle Proteins; D003676:Deferoxamine; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D016328:NF-kappa B; D019869:Phosphatidylinositol 3-Kinases; D016601:RNA-Binding Proteins; D013882:Thiosemicarbazones; D014409:Tumor Necrosis Factor-alpha; D014746:Vimentin; D000099259:N-myc Downstream-Regulated Gene 1 Protein; C483039:MTDH protein, human