Molecular functions of the iron-regulated metastasis suppressor, NDRG1, and its potential as a molecular target for cancer therapy

Fang, Bernard; Kovačević, Žaklina; Park, Kyung Chan; Kalinowski, Danuta S.; Jansson, Patric J.; Lane, Darius J.R.; Sahni, Sumit; Richardson, Des R.

doi:10.1016/j.bbcan.2013.11.002

Cited by 104 publications

(161 citation statements)

References 259 publications

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“…N-myc downstream regulated gene 1 (NDRG1) is a predominantly cytoplasmic 43-kDa protein that is upregulated by cellular iron depletion (Le and Richardson, 2004;Kovacevic et al, 2008;Fang et al, 2014). A number of studies examining the role of NDRG1 in vivo and in patient specimens have demonstrated that NDRG1 acts as a potent metastasis suppressor in a number of different tumor types (Bandyopadhyay et al, 2003(Bandyopadhyay et al, , 2004Shah et al, 2005;Maruyama et al, 2006;Dixon et al, 2013;Kovacevic et al, 2013Kovacevic et al, , 2016Sun et al, 2013a, b;Jin et al, 2014;Liu et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

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

Wangpu

Lü

et al. 2016

Mol Pharmacol

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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.

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Section: Introductionmentioning

confidence: 99%

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

Wangpu

Lü

et al. 2016

Mol Pharmacol

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“…In fact, a variety of studies have revealed a negative correlation between NDRG1 expression and cancer grade and spread, indicating its role as a suppressor of metastasis (Fang et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

The metastasis suppressor, NDRG1, modulates β-Catenin phosphorylation and nuclear translocation by mechanisms involving FRAT1 and PAK4

Jin¹,

Liu²,

Menezes³

et al. 2014

Journal of Cell Science

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N-myc downstream-regulated gene 1 (NDRG1) is a potent metastasis suppressor that has been demonstrated to inhibit the transforming growth factor b (TGF-b)-induced epithelial-tomesenchymal transition (EMT) by maintaining the cell-membrane localization of E-cadherin and b-catenin in prostate and colon cancer cells. However, the precise molecular mechanism remains unclear. In this investigation, we demonstrate that NDRG1 inhibits the phosphorylation of b-catenin at Ser33/37 and Thr41 and increases the levels of non-phosphorylated b-catenin at the plasma membrane in DU145 prostate cancer cells and HT29 colon cancer cells. The mechanism of inhibiting b-catenin phosphorylation involves the NDRG1-mediated upregulation of the GSK3b-binding protein FRAT1, which prevents the association of GSK3b with the Axin1-APC-CK1 destruction complex and the subsequent phosphorylation of b-catenin. Additionally, NDRG1 is shown to modulate the WNT-b-catenin pathway by inhibiting the nuclear translocation of b-catenin. This is mediated through an NDRG1-dependent reduction in the nuclear localization of p21-activated kinase 4 (PAK4), which is known to act as a transporter for b-catenin nuclear translocation. The current study is the first to elucidate a unique molecular mechanism involved in the NDRG1-dependent regulation of b-catenin phosphorylation and distribution.

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“…In fact, studies examining the prognosis of patients with these latter neoplasms demonstrated that those with higher NDRG1 levels had a significantly better outcome when compared with those with low NDRG1 levels (5,(11)(12)(13). Hence, NDRG1 is a promising prognostic indicator and molecular target for these cancers (14), which represent some of the most common and fatal neoplastic conditions. The molecular functions of NDRG1 have been the subject of increasing interest in recent years, with studies demonstrating that this metastasis suppressor is involved in numerous signaling pathways that regulate cancer cell proliferation, invasion, angiogenesis, and migration (7,9,14,15).…”

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“…Hence, NDRG1 is a promising prognostic indicator and molecular target for these cancers (14), which represent some of the most common and fatal neoplastic conditions. The molecular functions of NDRG1 have been the subject of increasing interest in recent years, with studies demonstrating that this metastasis suppressor is involved in numerous signaling pathways that regulate cancer cell proliferation, invasion, angiogenesis, and migration (7,9,14,15). Specifically, NDRG1 inhibited the oncogenic RAS, c-Src, phosphatidylinositol 3-kinase (PI3K), WNT, ROCK1/pMLC2, and nuclear factor -light chain enhancer of activated B cell (NF-B) pathways, while promoting expression of key tumor-suppressive molecules such as phosphatase and tensin homolog, E-cadherin, and mothers against decapentaplegic homolog 4 (SMAD4) (4, 6, 8, 16 -20).…”

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confidence: 99%

“…The pathways targeted by the ErbB receptors are dictated by the dimer partners, as each member of this receptor family has distinct biochemical properties and binding partners (27,28). Some of the downstream pathways affected by the EGFR, HER2, and HER3 receptors include the PI3K, RAS, MAPK, WNT, TGF-␤, NF-B, and c-Src pathways (28,35), many of which have been previously shown to be modulated by NDRG1 expression (2,6,8,11,14,(17)(18)(19). Hence, we hypothesized that NDRG1 may potentially affect a wide array of pathways by targeting the ErbB family members.…”

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The Metastasis Suppressor, N-MYC Downstream-regulated Gene-1 (NDRG1), Down-regulates the ErbB Family of Receptors to Inhibit Downstream Oncogenic Signaling Pathways

Kovačević

Menezes

Sahni

et al. 2016

Journal of Biological Chemistry

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113

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N-MYC downstream-regulated gene-1 (NDRG1) is a potent growth and metastasis suppressor that acts through its inhibitory effects on a wide variety of cellular signaling pathways, including the TGF-␤ pathway, protein kinase B (AKT)/PI3K pathway, RAS, etc. To investigate the hypothesis that its multiple effects could be regulated by a common upstream effector, the role of NDRG1 on the epidermal growth factor receptor (EGFR) and other members of the ErbB family, namely human epidermal growth factor receptor 2 (HER2) and human epidermal growth factor receptor 3 (HER3), was examined. We demonstrate that NDRG1 markedly decreased the expression and activation of EGFR, HER2, and HER3 in response to the epidermal growth factor (EGF) ligand, while also inhibiting formation of the EGFR/HER2 and HER2/HER3 heterodimers. In addition, NDRG1 also decreased activation of the downstream MAPKK in response to EGF. Moreover, novel anti-tumor agents of the di-2-pyridylketone class of thiosemicarbazones, namely di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone and di-2-pyridylketone 4-cyclohexyl-4-methyl-3-thiosemicarbazone, which markedly up-regulate NDRG1, were found to inhibit EGFR, HER2, and HER3 expression and phosphorylation in cancer cells. However, the mechanism involved appeared dependent on NDRG1 for di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone, but was independent of this metastasis suppressor for di-2-pyridylketone 4-cyclohexyl-4-methyl-3-thiosemicarbazone. This observation demonstrates that small structural changes in thiosemicarbazones result in marked alterations in molecular targeting. Collectively, these results reveal a mechanism for the extensive downstream effects on cellular signaling attributed to NDRG1. Furthermore, this study identifies a novel approach for the treatment of tumors resistant to traditional EGFR inhibitors.

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Molecular functions of the iron-regulated metastasis suppressor, NDRG1, and its potential as a molecular target for cancer therapy

Cited by 104 publications

References 259 publications

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

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

The metastasis suppressor, NDRG1, modulates β-Catenin phosphorylation and nuclear translocation by mechanisms involving FRAT1 and PAK4

The Metastasis Suppressor, N-MYC Downstream-regulated Gene-1 (NDRG1), Down-regulates the ErbB Family of Receptors to Inhibit Downstream Oncogenic Signaling Pathways

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