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.
Footnotes
- Received February 14, 2016.
- Accepted February 17, 2016.
M.Z., Z.K. and D.R.R. contributed equally as co-corresponding authors.
This work was supported by a PhD Scholarship from the China Scholarship Council, National Health and Medical Research Council of Australia (NHMRC) Senior Principal Research Fellowship [APP1062607], NHMRC Project Grant [APP1060482], NHMRC Australian Training Fellowship [APP1037323], Cancer Institute New South Wales Early Career Development Fellowship [12/ECF/2-17], National Natural Science Foundation of China Project Grants [81201539, 81201625, 81402423], Science and Technology Commission of Shanghai Municipality Project Grants [13JC1404100, 11411950700], and National High Technology Research and Development Program 863 Project Grant [2012AA021103].
D. R. R. consults and is a stakeholder in the companies, Oncochel Therapeutics LLC and Pty. Ltd, which are developing DpC for the treatment of advanced and resistant solid tumors.
- Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics
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