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

Molecular Pharmacology
Xiongzhi WangpuDes R Richardson

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...Continue Reading

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Citations

Jan 18, 2018·Antioxidants & Redox Signaling·Petra HeffeterChristian R Kowol
Oct 19, 2017·Pediatric Hematology and Oncology·Panagiotis KratimenosStamatios Theocharis
Jul 8, 2017·Current Medicinal Chemistry·Angelica M MerlotDes R Richardson
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Apr 3, 2020·International Journal of Molecular Medicine·Jun WanYupeng Liu
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Jun 25, 2020·Cancer Metastasis Reviews·Belinda J Petri, Carolyn M Klinge
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Jun 7, 2018·British Journal of Cancer·César RiveraAdriana Franco Paes Leme
Jul 28, 2020·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Syer C LimZaklina Kovacevic

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