The Iron-Regulated Metastasis Suppressor NDRG1 Targets NEDD4L, PTEN, and SMAD4 and Inhibits the PI3K and Ras Signaling Pathways

Kovačević, Žaklina; Chikhani, Sherin; Lui, Goldie Y.L.; Sivagurunathan, Sutharshani; Richardson, Des R.

doi:10.1089/ars.2011.4273

Cited by 155 publications

(205 citation statements)

References 42 publications

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“…Inc.) with 10% fetal calf serum (Life Technologies, Inc.) and cultured by standard procedures (4) for less than 3 months after resuscitation. PANC-1 and HT-29 cells were stably transfected to overexpress NDRG1 and compared with an empty vector-transfected control, as described previously (4,8). The transfected PANC-1 and HT-29 cells were maintained in DMEM and McCoy's 5A medium containing G418 (500 g/ml; Sigma), respectively.…”

Section: Methodsmentioning

confidence: 99%

“…and HT-29 Cells-Considering that multiple cell signaling pathways are markedly affected by the metastasis suppressor, NDRG1, in both PANC-1 pancreatic and HT-29 colon cancer cells (4,8,17,20), these latter cell types were utilized to examine whether NDRG1 affected EGFR expression and activation. This was important to establish, as EGFR is a key regulator of numerous oncogenic downstream signaling pathways (31,43) that were previously found to be inhibited by NDRG1 (4,6,8,(17)(18)(19).…”

Section: Ndrg1 Down-regulates the Expression Of Egfr In Panc-1mentioning

confidence: 99%

“…This was important to establish, as EGFR is a key regulator of numerous oncogenic downstream signaling pathways (31,43) that were previously found to be inhibited by NDRG1 (4,6,8,(17)(18)(19). Considering the differences between tumors regarding their genetic background, all studies were conducted with both cell lines, to gain insight into NDRG1 function and gauge common functions between cell types.…”

Section: Ndrg1 Down-regulates the Expression Of Egfr In Panc-1mentioning

confidence: 99%

“…In fact, we and others recently demonstrated that NDRG1 can be markedly up-regulated by a novel class of anti-cancer agents, namely the di-2-pyridylketone class of thiosemicarbazones, such as di-2-pyri-dylketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT) 8 and di-2-pyridylketone 4-cyclohexyl-4-methyl-3-thiosemicarbazone (DpC; Fig. 1A) (1,3,18,(21)(22)(23).…”

mentioning

confidence: 98%

“…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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confidence: 99%

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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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Section: Methodsmentioning

confidence: 99%

Section: Ndrg1 Down-regulates the Expression Of Egfr In Panc-1mentioning

confidence: 99%

Section: Ndrg1 Down-regulates the Expression Of Egfr In Panc-1mentioning

confidence: 99%

mentioning

confidence: 98%

mentioning

confidence: 99%

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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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Potent ribonucleotide reductase inhibitors: Thiazole‐containing thiosemicarbazone derivatives

Ertaş

Şahin

Bülbül

et al. 2019

Archiv der Pharmazie

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The antioxidant, antimalarial, antibacterial, and antitumor activities of thiosemicarbazones have made this class of compounds important for medicinal chemists. In addition, thiosemicarbazones are among the most potent and well-known ribonucleotide reductase inhibitors. In this study, 24 new thiosemicarbazone derivatives were synthesized, and the structures and purity of the compounds were determined by IR, 1 H NMR, 13 C NMR, mass spectroscopy, and elemental analysis. The IC 50 values of these 24 compounds were determined with an assay for ribonucleotide reductase inhibition. Compounds 19, 20, and 24 inhibited ribonucleotide reductase enzyme activity at a higher level than metisazone as standard. The cytotoxic effects of these compounds were measured on the MCF7 (human breast adenocarcinoma) and HEK293 (human embryonic kidney) cell lines. Similarly, compounds 19, 20, and 24 had a selective effect on the MCF7 and HEK293 cell lines, killing more cancer cells than cisplatin as standard. The compounds (especially 19, 20, and 24 as the most active ones) were then subjected to docking experiments to identify the probable interactions between the ligands and the enzyme active site. The complex formation was shown qualitatively. The ADME (absorption, distribution, metabolism, and excretion) properties of the compounds were analyzed using in-silico techniques.

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Knockdown of NDRG1 promote epithelial-mesenchymal transition of colorectal cancer via NF-κB signaling

Gao

Zeng

et al. 2016

J. Surg. Oncol.

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The Iron-Regulated Metastasis Suppressor NDRG1 Targets NEDD4L, PTEN, and SMAD4 and Inhibits the PI3K and Ras Signaling Pathways

Abstract: The identified target genes of NDRG1 and their effect on the TGF-β signaling pathway reveal its molecular function in pancreatic cancer and a novel therapeutic avenue.

Cited by 155 publications

References 42 publications

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

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

Potent ribonucleotide reductase inhibitors: Thiazole‐containing thiosemicarbazone derivatives

Knockdown of NDRG1 promote epithelial-mesenchymal transition of colorectal cancer via NF-κB signaling

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