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

Xiongzhi Wangpu; Jiaoyang Lu; Ruxing Xi; Fei Yue; Sumit Sahni; Kyung Chan Park; Sharleen Menezes; Michael L H Huang; Minhua Zheng; Zaklina Kovacevic; Des R Richardson

doi:10.1124/mol.115.103044

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

Mol Pharmacol. 2016 May;89(5):521-40. doi: 10.1124/mol.115.103044. Epub 2016 Feb 19.

Authors

Affiliations

¹ 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.).
² 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.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / pharmacology
Cell Adhesion / drug effects
Cell Cycle Proteins / antagonists & inhibitors
Cell Cycle Proteins / genetics
Cell Cycle Proteins / metabolism*
Cell Line, Tumor
Cell Movement / drug effects
Collagen / metabolism
Colonic Neoplasms / drug therapy
Colonic Neoplasms / metabolism*
Colonic Neoplasms / pathology
Enzyme Activation / drug effects
Focal Adhesion Kinase 1 / antagonists & inhibitors
Focal Adhesion Kinase 1 / chemistry
Focal Adhesion Kinase 1 / genetics
Focal Adhesion Kinase 1 / metabolism*
Focal Adhesions / drug effects
Focal Adhesions / metabolism
Focal Adhesions / pathology
Humans
Intracellular Signaling Peptides and Proteins / antagonists & inhibitors
Intracellular Signaling Peptides and Proteins / genetics
Intracellular Signaling Peptides and Proteins / metabolism*
Male
Neoplasm Proteins / agonists
Neoplasm Proteins / antagonists & inhibitors
Neoplasm Proteins / genetics
Neoplasm Proteins / metabolism
Paxillin / agonists
Paxillin / antagonists & inhibitors
Paxillin / metabolism*
Phosphorylation / drug effects
Prostatic Neoplasms / drug therapy
Prostatic Neoplasms / metabolism*
Prostatic Neoplasms / pathology
Protein Kinase Inhibitors / pharmacology
Protein Processing, Post-Translational* / drug effects
Pyridines / pharmacology
RNA Interference
Recombinant Proteins / chemistry
Recombinant Proteins / metabolism
Signal Transduction* / drug effects
Thiosemicarbazones / pharmacology

Substances

Antineoplastic Agents
Cell Cycle Proteins
Intracellular Signaling Peptides and Proteins
N-myc downstream-regulated gene 1 protein
Neoplasm Proteins
PXN protein, human
Paxillin
Protein Kinase Inhibitors
Pyridines
Recombinant Proteins
Thiosemicarbazones
di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone
di-2-pyridylketone 4-cyclohexyl-4-methyl-3-thiosemicarbazone
Collagen
Focal Adhesion Kinase 1
PTK2 protein, human