title: Targeting the Metastasis Suppressor, N-Myc Downstream Regulated Gene-1, with Novel Di-2-Pyridylketone Thiosemicarbazones: Suppression of Tumor Cell Migration and Cell-Collagen Adhesion by Inhibiting Focal Adhesion Kinase/Paxillin Signaling.
abstract: Metastasis is a complex process that is regulated by multiple signaling pathways, with the focal adhesion kinase (FAK)/paxillin pathway playing a major role in the formation of focal adhesions and cell motility. N-myc downstream regulated gene-1 (NDRG1) is a potent metastasis suppressor in many solid tumor types, including prostate and colon cancer. Considering the antimetastatic effect of NDRG1 and the crucial involvement of the FAK/paxillin pathway in cellular migration and cell-matrix adhesion, we assessed the effects of NDRG1 on this important oncogenic pathway. In the present study, NDRG1 overexpression and silencing models of HT29 colon cancer and DU145 prostate cancer cells were used to examine the activation of FAK/paxillin signaling and the formation of focal adhesions. The expression of NDRG1 resulted in a marked and significant decrease in the activating phosphorylation of FAK and paxillin, whereas silencing of NDRG1 resulted in an opposite effect. The expression of NDRG1 also inhibited the formation of focal adhesions as well as cell migration and cell-collagen adhesion. Incubation of cells with novel thiosemicarbazones, namely di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone and di-2-pyridylketone 4-cyclohexyl-4-methyl-3-thiosemicarbazone, that upregulate NDRG1 also resulted in decreased phosphorylation of FAK and paxillin. The ability of these thiosemicarbazones to inhibit cell migration and metastasis could be mediated, at least in part, through the FAK/paxillin pathway.
authors.affiliation: Department of General Surgery; Shanghai Minimally Invasive Surgery Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China (X.W., J.L., F.Y., M.Z.); Department of Pathology and Bosch Institute, University of Sydney, New South Wales, Australia (X.W., R.X., S.S., K.C.P., S.M., M.L.H.H., Z.K., D.R.R.); and Department of Radiotherapy, The First Affiliated Hospital of Xi'an Jiao Tong University, Xi'an, China (R.X.).
authors.forename: Xiongzhi
authors.initials: X
authors.lastname: Wangpu
authors.affiliation: Department of General Surgery; Shanghai Minimally Invasive Surgery Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China (X.W., J.L., F.Y., M.Z.); Department of Pathology and Bosch Institute, University of Sydney, New South Wales, Australia (X.W., R.X., S.S., K.C.P., S.M., M.L.H.H., Z.K., D.R.R.); and Department of Radiotherapy, The First Affiliated Hospital of Xi'an Jiao Tong University, Xi'an, China (R.X.).
authors.forename: Jiaoyang
authors.initials: J
authors.lastname: Lu
authors.affiliation: Department of General Surgery; Shanghai Minimally Invasive Surgery Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China (X.W., J.L., F.Y., M.Z.); Department of Pathology and Bosch Institute, University of Sydney, New South Wales, Australia (X.W., R.X., S.S., K.C.P., S.M., M.L.H.H., Z.K., D.R.R.); and Department of Radiotherapy, The First Affiliated Hospital of Xi'an Jiao Tong University, Xi'an, China (R.X.).
authors.forename: Ruxing
authors.initials: R
authors.lastname: Xi
authors.affiliation: Department of General Surgery; Shanghai Minimally Invasive Surgery Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China (X.W., J.L., F.Y., M.Z.); Department of Pathology and Bosch Institute, University of Sydney, New South Wales, Australia (X.W., R.X., S.S., K.C.P., S.M., M.L.H.H., Z.K., D.R.R.); and Department of Radiotherapy, The First Affiliated Hospital of Xi'an Jiao Tong University, Xi'an, China (R.X.).
authors.forename: Fei
authors.initials: F
authors.lastname: Yue
authors.affiliation: Department of General Surgery; Shanghai Minimally Invasive Surgery Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China (X.W., J.L., F.Y., M.Z.); Department of Pathology and Bosch Institute, University of Sydney, New South Wales, Australia (X.W., R.X., S.S., K.C.P., S.M., M.L.H.H., Z.K., D.R.R.); and Department of Radiotherapy, The First Affiliated Hospital of Xi'an Jiao Tong University, Xi'an, China (R.X.).
authors.forename: Sumit
authors.initials: S
authors.lastname: Sahni
authors.affiliation: Department of General Surgery; Shanghai Minimally Invasive Surgery Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China (X.W., J.L., F.Y., M.Z.); Department of Pathology and Bosch Institute, University of Sydney, New South Wales, Australia (X.W., R.X., S.S., K.C.P., S.M., M.L.H.H., Z.K., D.R.R.); and Department of Radiotherapy, The First Affiliated Hospital of Xi'an Jiao Tong University, Xi'an, China (R.X.).
authors.forename: Kyung Chan
authors.initials: KC
authors.lastname: Park
authors.affiliation: Department of General Surgery; Shanghai Minimally Invasive Surgery Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China (X.W., J.L., F.Y., M.Z.); Department of Pathology and Bosch Institute, University of Sydney, New South Wales, Australia (X.W., R.X., S.S., K.C.P., S.M., M.L.H.H., Z.K., D.R.R.); and Department of Radiotherapy, The First Affiliated Hospital of Xi'an Jiao Tong University, Xi'an, China (R.X.).
authors.forename: Sharleen
authors.initials: S
authors.lastname: Menezes
authors.affiliation: Department of General Surgery; Shanghai Minimally Invasive Surgery Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China (X.W., J.L., F.Y., M.Z.); Department of Pathology and Bosch Institute, University of Sydney, New South Wales, Australia (X.W., R.X., S.S., K.C.P., S.M., M.L.H.H., Z.K., D.R.R.); and Department of Radiotherapy, The First Affiliated Hospital of Xi'an Jiao Tong University, Xi'an, China (R.X.).
authors.forename: Michael L H
authors.initials: ML
authors.lastname: Huang
authors.affiliation: Department of General Surgery; Shanghai Minimally Invasive Surgery Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China (X.W., J.L., F.Y., M.Z.); Department of Pathology and Bosch Institute, University of Sydney, New South Wales, Australia (X.W., R.X., S.S., K.C.P., S.M., M.L.H.H., Z.K., D.R.R.); and Department of Radiotherapy, The First Affiliated Hospital of Xi'an Jiao Tong University, Xi'an, China (R.X.).
authors.forename: Minhua
authors.initials: M
authors.lastname: Zheng
authors.affiliation: Department of General Surgery; Shanghai Minimally Invasive Surgery Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China (X.W., J.L., F.Y., M.Z.); Department of Pathology and Bosch Institute, University of Sydney, New South Wales, Australia (X.W., R.X., S.S., K.C.P., S.M., M.L.H.H., Z.K., D.R.R.); and Department of Radiotherapy, The First Affiliated Hospital of Xi'an Jiao Tong University, Xi'an, China (R.X.) d.richardson@med.usyd.edu.au zaklina.kovacevic@sydney.edu.au zmhtiger@yeah.net.
authors.forename: Zaklina
authors.initials: Z
authors.lastname: Kovacevic
authors.affiliation: Department of General Surgery; Shanghai Minimally Invasive Surgery Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China (X.W., J.L., F.Y., M.Z.); Department of Pathology and Bosch Institute, University of Sydney, New South Wales, Australia (X.W., R.X., S.S., K.C.P., S.M., M.L.H.H., Z.K., D.R.R.); and Department of Radiotherapy, The First Affiliated Hospital of Xi'an Jiao Tong University, Xi'an, China (R.X.) d.richardson@med.usyd.edu.au zaklina.kovacevic@sydney.edu.au zmhtiger@yeah.net.
authors.forename: Des R
authors.initials: DR
authors.lastname: Richardson
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D002448:Cell Adhesion / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D003094:Collagen / Q000378:metabolism; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D004789:Enzyme Activation / Q000187:drug effects; D051417:Focal Adhesion Kinase 1 / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D022001:Focal Adhesions / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D008297:Male; D009363:Neoplasm Proteins / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D051419:Paxillin / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology; D034622:RNA Interference; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013882:Thiosemicarbazones / Q000494:pharmacology; D000099259:N-myc Downstream-Regulated Gene 1 Protein
chemical_list: D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D003094:Collagen; D051417:Focal Adhesion Kinase 1; D047908:Intracellular Signaling Peptides and Proteins; D009363:Neoplasm Proteins; D051419:Paxillin; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D011994:Recombinant Proteins; D013882:Thiosemicarbazones; D000099259:N-myc Downstream-Regulated Gene 1 Protein; C496061:PXN protein, human; C539263:di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone; C000607942:di-2-pyridylketone 4-cyclohexyl-4-methyl-3-thiosemicarbazone; C496050:PTK2 protein, human