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• W2625660736 abstract "The iron-regulated metastasis suppressor N-myc downstream-regulated gene 1 (NDRG1) has been shown to inhibit numerous oncogenic signaling pathways in cancer cells. Recent findings have demonstrated that NDRG1 inhibits the ErbB family of receptors, which function as key inducers of carcinogenesis. NDRG1 attenuates ErbB signaling by inhibiting formation of epidermal growth factor receptor (EGFR)/human epidermal growth factor receptor 2 (HER2) and HER2/HER3 heterodimers and by down-regulating EGFR via a mechanism involving its degradation. Understanding the complex interplay between NDRG1, iron, and ErbB signaling is vital for identifying novel, more effective targets for cancer therapy. The iron-regulated metastasis suppressor N-myc downstream-regulated gene 1 (NDRG1) has been shown to inhibit numerous oncogenic signaling pathways in cancer cells. Recent findings have demonstrated that NDRG1 inhibits the ErbB family of receptors, which function as key inducers of carcinogenesis. NDRG1 attenuates ErbB signaling by inhibiting formation of epidermal growth factor receptor (EGFR)/human epidermal growth factor receptor 2 (HER2) and HER2/HER3 heterodimers and by down-regulating EGFR via a mechanism involving its degradation. Understanding the complex interplay between NDRG1, iron, and ErbB signaling is vital for identifying novel, more effective targets for cancer therapy. Metastasis is a multistep process that remains the leading cause of cancer-related deaths worldwide (1.Weigelt B. Peterse J.L. van't Veer L.J. Breast cancer metastasis: markers and models.Nat. Rev. Cancer. 2005; 5: 591-602Crossref PubMed Scopus (1691) Google Scholar). Beginning at the primary tumor site, cancer cells disseminate into the bloodstream and migrate to distant organs where they form secondary tumors (1.Weigelt B. Peterse J.L. van't Veer L.J. Breast cancer metastasis: markers and models.Nat. Rev. Cancer. 2005; 5: 591-602Crossref PubMed Scopus (1691) Google Scholar). Metastasis of these cells can be triggered by a plethora of biochemical factors and molecules as well as the extracellular environment (1.Weigelt B. Peterse J.L. van't Veer L.J. Breast cancer metastasis: markers and models.Nat. Rev. Cancer. 2005; 5: 591-602Crossref PubMed Scopus (1691) Google Scholar). Considering its key role in patient mortality, it is pertinent to understand how metastasis is regulated so as to design therapeutic modalities to inhibit cancer progression. This review specifically addresses the regulation of the metastasis suppressor N-myc downstream-regulated gene 1 (NDRG1) by iron and its associated downstream signaling pathways that have also been linked to iron homeostasis. This is important, as iron is crucial for tumor cell proliferation and metastasis (2.Fouani L. Menezes S.V. Paulson M. Richardson D.R. Kovacevic Z. Metals and metastasis: exploiting the role of metals in cancer metastasis to develop novel anti-metastatic agents.Pharmacol. Res. 2017; 115: 275-287Crossref PubMed Scopus (44) Google Scholar), and thus, it is vital to understand its role in oncogenic signaling. The molecule NDRG1 is a well-known metastasis suppressor that results in decreased metastases and improved patient prognosis in several cancer types, including those of the breast, prostate, pancreas, and colon (3.Fang B.A. Kovačevic Ž. Park K.C. Kalinowski D.S. Jansson P.J. Lane D.J. Sahni S. Richardson D.R. Molecular functions of the iron-regulated metastasis suppressor, NDRG1, and its potential as a molecular target for cancer therapy.Biochim. Biophys. Acta. 2014; 1845: 1-19PubMed Google Scholar, 4.Ellen T.P. Ke Q. Zhang P. Costa M. NDRG1, a growth and cancer related gene: regulation of gene expression and function in normal and disease states.Carcinogenesis. 2008; 29: 2-8Crossref PubMed Scopus (167) Google Scholar, 5.Kovacevic Z. Richardson D.R. The metastasis suppressor, Ndrg-1: a new ally in the fight against cancer.Carcinogenesis. 2006; 27: 2355-2366Crossref PubMed Scopus (158) Google Scholar). Paradoxically, NDRG1 expression is demonstrated to be increased in tumors of the liver, esophagus and cervix, where it stimulates oncogenesis (6.Chua M.S. Sun H. Cheung S.T. Mason V. Higgins J. Ross D.T. Fan S.T. So S. Overexpression of NDRG1 is an indicator of poor prognosis in hepatocellular carcinoma.Mod. Pathol. 2007; 20: 76-83Crossref PubMed Scopus (103) Google Scholar, 7.Nishio S. Ushijima K. Tsuda N. Takemoto S. Kawano K. Yamaguchi T. Nishida N. Kakuma T. Tsuda H. Kasamatsu T. Sasajima Y. Kage M. Kuwano M. Kamura T. Cap43/NDRG1/Drg-1 is a molecular target for angiogenesis and a prognostic indicator in cervical adenocarcinoma.Cancer Lett. 2008; 264: 36-43Crossref PubMed Scopus (66) Google Scholar, 8.Ai R. Sun Y. Guo Z. Wei W. Zhou L. Liu F. Hendricks D.T. Xu Y. Zhao X. NDRG1 overexpression promotes the progression of esophageal squamous cell carcinoma through modulating Wnt signaling pathway.Cancer Biol. Ther. 2016; 17: 943-954Crossref PubMed Scopus (33) Google Scholar), although in the majority of studies, it is associated with metastasis suppression (3.Fang B.A. Kovačevic Ž. Park K.C. Kalinowski D.S. Jansson P.J. Lane D.J. Sahni S. Richardson D.R. Molecular functions of the iron-regulated metastasis suppressor, NDRG1, and its potential as a molecular target for cancer therapy.Biochim. Biophys. Acta. 2014; 1845: 1-19PubMed Google Scholar, 5.Kovacevic Z. Richardson D.R. The metastasis suppressor, Ndrg-1: a new ally in the fight against cancer.Carcinogenesis. 2006; 27: 2355-2366Crossref PubMed Scopus (158) Google Scholar). In fact, NDRG1 has been recognized for its involvement in cellular signaling, growth, differentiation, lipid biosynthesis, and the stress response (3.Fang B.A. Kovačevic Ž. Park K.C. Kalinowski D.S. Jansson P.J. Lane D.J. Sahni S. Richardson D.R. Molecular functions of the iron-regulated metastasis suppressor, NDRG1, and its potential as a molecular target for cancer therapy.Biochim. Biophys. Acta. 2014; 1845: 1-19PubMed Google Scholar, 5.Kovacevic Z. Richardson D.R. The metastasis suppressor, Ndrg-1: a new ally in the fight against cancer.Carcinogenesis. 2006; 27: 2355-2366Crossref PubMed Scopus (158) Google Scholar). Most importantly, in its role as a potent metastasis suppressor, NDRG1 has been of great interest due to its ability to inhibit tumor growth and to decrease cell proliferation, migration, invasion, and angiogenesis (9.Kovacevic Z. Fu D. Richardson D.R. The iron-regulated metastasis suppressor, Ndrg-1: Identification of novel molecular targets.Biochim. Biophys. Acta. 2008; 1783: 1981-1992Crossref PubMed Scopus (66) Google Scholar, 10.Kovacevic Z. Sivagurunathan S. Mangs H. Chikhani S. Zhang D. Richardson D.R. The metastasis suppressor, N-myc downstream-regulated gene 1 (NDRG1), upregulates p21 via p53-independent mechanisms.Carcinogenesis. 2011; 32: 732-740Crossref PubMed Scopus (73) Google Scholar, 11.Chen J. Chen J.K. Nagai K. Plieth D. Tan M. Lee T.C. Threadgill D.W. Neilson E.G. Harris R.C. EGFR signaling promotes TGFβ-dependent renal fibrosis.J. Am. Soc. Nephrol. 2012; 23: 215-224Crossref PubMed Scopus (196) Google Scholar, 12.Sun J. Zhang D. Bae D.H. Sahni S. Jansson P. Zheng Y. Zhao Q. Yue F. Zheng M. Kovacevic Z. Richardson D.R. Metastasis supressor, NDRG1, mediates its activity through signaling pathways and molecular motors.Carcinogenesis. 2013; 34: 1943-1954Crossref PubMed Scopus (101) Google Scholar, 13.Kovacevic Z. Chikhani S. Lui G.Y. Sivagurunathan S. Richardson D.R. The iron-regulated metastasis suppressor NDRG1 targets NEDD4L, PTEN, and SMAD4 and inhibits the PI3K and Ras signaling pathways.Antioxid. Redox Signal. 2013; 18: 874-887Crossref PubMed Scopus (127) Google Scholar, 14.Jin R. Liu W. Menezes S. Yue F. Zheng M. Kovacevic Z. Richardson D.R. The metastasis suppressor, NDRG1, modulates β-catenin phosphorylation and nuclear translocation by mechanisms involving FRAT1 and PAK4.J. Cell Sci. 2014; 127: 3116-3130Crossref PubMed Scopus (89) Google Scholar, 15.Liu W. Yue F. Zheng M. Merlot A. Bae D.H. Huang M. Lane D. Jansson P. Lui G.Y. Richardson V. Sahni S. Kalinowski D. Kovacevic Z. Richardson D.R. The proto-oncogene c-Src and its downstream signaling pathways are inhibited by the metastasis suppressor, NDRG1.Oncotarget. 2015; 6: 8851-8874Crossref PubMed Scopus (59) Google Scholar, 16.Wangpu X. Lu J. Xi R. Yue F. Sahni S. Park K.C. Menezes S. Huang M.L. Zheng M. Kovacevic Z. Richardson D.R. 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; 89: 521-540Crossref PubMed Scopus (42) Google Scholar, 17.Kovacevic Z. Menezes S.V. Sahni S. Kalinowski D.S. Bae D.H. Lane D.J. Richardson D.R. The metastasis suppressor, N-MYC downstream-regulated gene-1 (NDRG1), down-regulates the ErbB family of receptors to inhibit downstream oncogenic signaling pathways.J. Biol. Chem. 2016; 291: 1029-1052Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar, 18.Liu W. Xing F. Iiizumi-Gairani M. Okuda H. Watabe M. Pai S.K. Pandey P.R. Hirota S. Kobayashi A. Mo Y.Y. Fukuda K. Li Y. Watabe K. N-myc downstream regulated gene 1 modulates Wnt-β-catenin signalling and pleiotropically suppresses metastasis.EMBO Mol. Med. 2012; 4: 93-108Crossref PubMed Scopus (153) Google Scholar, 19.Hosoi F. Izumi H. Kawahara A. Murakami Y. Kinoshita H. Kage M. Nishio K. Kohno K. Kuwano M. Ono M. N-myc downstream regulated gene 1/Cap43 suppresses tumor growth and angiogenesis of pancreatic cancer through attenuation of inhibitor of κB kinase β expression.Cancer Res. 2009; 69: 4983-4991Crossref PubMed Scopus (84) Google Scholar). Recently, the roles of LSD1 and N-myc in the regulation of NDRG1 expression were investigated, and it was shown that LSD1 co-localizes with N-myc at the promoter region of the NDRG1 gene to inhibit its expression (20.Ambrosio S. Amente S. Saccà C.D. Capasso M. Calogero R.A. Lania L. Majello B. LSD1 mediates MYCN control of epithelial-mesenchymal transition through silencing of metastatic suppressor NDRG1 gene.Oncotarget. 2017; 8: 3854-3869Crossref PubMed Scopus (30) Google Scholar). Furthermore, it is well known that NDRG1 is a hypoxia-regulated gene and can be induced by hypoxic conditions via an HIF-1α (hypoxia-inducible factor-1α)-dependent mechanism (21.Le N.T. Richardson D.R. Iron chelators with high antiproliferative activity up-regulate the expression of a growth inhibitory and metastasis suppressor gene: a link between iron metabolism and proliferation.Blood. 2004; 104: 2967-2975Crossref PubMed Scopus (257) Google Scholar). It has also been demonstrated that NDRG1 expression is regulated by intracellular iron in a wide variety of studies in vitro and in vivo (9.Kovacevic Z. Fu D. Richardson D.R. The iron-regulated metastasis suppressor, Ndrg-1: Identification of novel molecular targets.Biochim. Biophys. Acta. 2008; 1783: 1981-1992Crossref PubMed Scopus (66) Google Scholar, 13.Kovacevic Z. Chikhani S. Lui G.Y. Sivagurunathan S. Richardson D.R. The iron-regulated metastasis suppressor NDRG1 targets NEDD4L, PTEN, and SMAD4 and inhibits the PI3K and Ras signaling pathways.Antioxid. Redox Signal. 2013; 18: 874-887Crossref PubMed Scopus (127) Google Scholar, 15.Liu W. Yue F. Zheng M. Merlot A. Bae D.H. Huang M. Lane D. Jansson P. Lui G.Y. Richardson V. Sahni S. Kalinowski D. Kovacevic Z. Richardson D.R. The proto-oncogene c-Src and its downstream signaling pathways are inhibited by the metastasis suppressor, NDRG1.Oncotarget. 2015; 6: 8851-8874Crossref PubMed Scopus (59) Google Scholar, 16.Wangpu X. Lu J. Xi R. Yue F. Sahni S. Park K.C. Menezes S. Huang M.L. Zheng M. Kovacevic Z. Richardson D.R. 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; 89: 521-540Crossref PubMed Scopus (42) Google Scholar, 21.Le N.T. Richardson D.R. Iron chelators with high antiproliferative activity up-regulate the expression of a growth inhibitory and metastasis suppressor gene: a link between iron metabolism and proliferation.Blood. 2004; 104: 2967-2975Crossref PubMed Scopus (257) Google Scholar, 22.Lane D.J. Saletta F. Suryo Rahmanto Y. Kovacevic Z. Richardson D.R. N-myc downstream regulated 1 (NDRG1) is regulated by eukaryotic initiation factor 3a (eIF3a) during cellular stress caused by iron depletion.PLoS ONE. 2013; 8: e57273Crossref PubMed Scopus (53) Google Scholar, 23.Chen Z. Zhang D. Yue F. Zheng M. Kovacevic Z. Richardson D.R. The iron chelators Dp44mT and DFO inhibit TGF-β-induced epithelial-mesenchymal transition via up-regulation of N-Myc downstream-regulated gene 1 (NDRG1).J. Biol. Chem. 2012; 287: 17016-17028Abstract Full Text Full Text PDF PubMed Scopus (194) Google Scholar, 24.Sun J. Zhang D. Zheng Y. Zhao Q. Zheng M. Kovacevic Z. Richardson D.R. Targeting the metastasis suppressor, NDRG1, using novel iron chelators: regulation of stress fiber-mediated tumor cell migration via modulation of the ROCK1/pMLC2 signaling pathway.Mol. Pharmacol. 2013; 83: 454-469Crossref PubMed Scopus (82) Google Scholar, 25.Dixon K.M. Lui G.Y. Kovacevic Z. Zhang D. Yao M. Chen Z. Dong Q. Assinder S.J. Richardson D.R. Dp44mT targets the AKT, TGF-β and ERK pathways via the metastasis suppressor NDRG1 in normal prostate epithelial cells and prostate cancer cells.Br. J. Cancer. 2013; 108: 409-419Crossref PubMed Scopus (88) Google Scholar, 26.Whitnall M. Howard J. Ponka P. Richardson D.R. A class of iron chelators with a wide spectrum of potent antitumor activity that overcomes resistance to chemotherapeutics.Proc. Natl. Acad. Sci. U.S.A. 2006; 103: 14901-14906Crossref PubMed Scopus (425) Google Scholar, 27.Saletta F. Suryo Rahmanto Y. Noulsri E. Richardson D.R. Iron chelator-mediated alterations in gene expression: identification of novel iron-regulated molecules that are molecular targets of hypoxia-inducible factor-1α and p53.Mol. Pharmacol. 2010; 77: 443-458Crossref PubMed Scopus (62) Google Scholar, 28.Kovacevic Z. Chikhani S. Lovejoy D.B. Richardson D.R. Novel thiosemicarbazone iron chelators induce up-regulation and phosphorylation of the metastasis suppressor N-myc downstream regulated gene 1: a new strategy for the treatment of pancreatic cancer.Mol. Pharmacol. 2011; 80: 598-609Crossref PubMed Scopus (145) Google Scholar, 29.Hickok J.R. Sahni S. Mikhed Y. Bonini M.G. Thomas D.D. Nitric oxide suppresses tumor cell migration through N-Myc Downstream-regulated Gene-1 (NDRG1) expression: role of chelatable iron.J. Biol. Chem. 2011; 286: 41413-41424Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar, 30.Salnikow K. Li X. Lippmann M. Effect of nickel and iron co-exposure on human lung cells.Toxicol. Appl. Pharmacol. 2004; 196: 258-265Crossref PubMed Scopus (43) Google Scholar, 31.Zhang P. Tchou-Wong K.M. Costa M. Egr-1 mediates hypoxia-inducible transcription of the NDRG1 gene through an overlapping Egr-1/Sp1 binding site in the promoter.Cancer Res. 2007; 67: 9125-9133Crossref PubMed Scopus (60) Google Scholar). In fact, a decrease in cellular iron results in robust up-regulation of NDRG1 at the mRNA and protein level, whereas supplementation of iron leads to decreased NDRG1 expression (21.Le N.T. Richardson D.R. Iron chelators with high antiproliferative activity up-regulate the expression of a growth inhibitory and metastasis suppressor gene: a link between iron metabolism and proliferation.Blood. 2004; 104: 2967-2975Crossref PubMed Scopus (257) Google Scholar, 22.Lane D.J. Saletta F. Suryo Rahmanto Y. Kovacevic Z. Richardson D.R. N-myc downstream regulated 1 (NDRG1) is regulated by eukaryotic initiation factor 3a (eIF3a) during cellular stress caused by iron depletion.PLoS ONE. 2013; 8: e57273Crossref PubMed Scopus (53) Google Scholar, 27.Saletta F. Suryo Rahmanto Y. Noulsri E. Richardson D.R. Iron chelator-mediated alterations in gene expression: identification of novel iron-regulated molecules that are molecular targets of hypoxia-inducible factor-1α and p53.Mol. Pharmacol. 2010; 77: 443-458Crossref PubMed Scopus (62) Google Scholar). As an appropriate positive control, the same regulation was also reported for other classical iron-regulated molecules, e.g. the TfR1 4The abbreviations used are: TfR1transferrin receptor 13112-hydroxyl-1-naphthaldehyde isonicotinoyl hydrazoneBTCbetacellulinDFOdesferrioxamineDp44mT2-pyridylketone 4,4-dimethyl-3-thiosemicarbazoneDpCdi-2-pyridylketone 4-cyclohexyl-4-methyl-3-thiosemicarbazoneEGFRepidermal growth factor receptorEMTepithelial to mesenchymal transitionNRGneuregulinp130CasCrk-associated substratePTENphosphatase and tensin homologueRafrapidly accelerated fibrosarcomaTftransferrinFAKfocal adhesion kinase. (transferrin receptor 1), VEGF1 (vascular endothelial growth factor 1), etc., confirming the physiological nature of the iron depletion reported (21.Le N.T. Richardson D.R. Iron chelators with high antiproliferative activity up-regulate the expression of a growth inhibitory and metastasis suppressor gene: a link between iron metabolism and proliferation.Blood. 2004; 104: 2967-2975Crossref PubMed Scopus (257) Google Scholar, 22.Lane D.J. Saletta F. Suryo Rahmanto Y. Kovacevic Z. Richardson D.R. N-myc downstream regulated 1 (NDRG1) is regulated by eukaryotic initiation factor 3a (eIF3a) during cellular stress caused by iron depletion.PLoS ONE. 2013; 8: e57273Crossref PubMed Scopus (53) Google Scholar, 27.Saletta F. Suryo Rahmanto Y. Noulsri E. Richardson D.R. Iron chelator-mediated alterations in gene expression: identification of novel iron-regulated molecules that are molecular targets of hypoxia-inducible factor-1α and p53.Mol. Pharmacol. 2010; 77: 443-458Crossref PubMed Scopus (62) Google Scholar). transferrin receptor 1 2-hydroxyl-1-naphthaldehyde isonicotinoyl hydrazone betacellulin desferrioxamine 2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone di-2-pyridylketone 4-cyclohexyl-4-methyl-3-thiosemicarbazone epidermal growth factor receptor epithelial to mesenchymal transition neuregulin Crk-associated substrate phosphatase and tensin homologue rapidly accelerated fibrosarcoma transferrin focal adhesion kinase. Critically, the up-regulation of NDRG1 occurs also in vivo in tumors after treatment of mice (intravenous) with the iron chelator, di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT) (26.Whitnall M. Howard J. Ponka P. Richardson D.R. A class of iron chelators with a wide spectrum of potent antitumor activity that overcomes resistance to chemotherapeutics.Proc. Natl. Acad. Sci. U.S.A. 2006; 103: 14901-14906Crossref PubMed Scopus (425) Google Scholar). This occurred concurrently in tumors with up-regulation of the TfR1 and also VEGF1 (26.Whitnall M. Howard J. Ponka P. Richardson D.R. A class of iron chelators with a wide spectrum of potent antitumor activity that overcomes resistance to chemotherapeutics.Proc. Natl. Acad. Sci. U.S.A. 2006; 103: 14901-14906Crossref PubMed Scopus (425) Google Scholar), both of which are classically known to be up-regulated by iron depletion (32.Torti S.V. Torti F.M. Iron and cancer: more ore to be mined.Nat. Rev. Cancer. 2013; 13: 342-355Crossref PubMed Scopus (952) Google Scholar). Dp44mT is a known iron chelator and results in cellular iron efflux and inhibits iron uptake from transferrin, leading to cellular iron depletion in vitro (33.Yuan J. Lovejoy D.B. Richardson D.R. Novel di-2-pyridyl-derived iron chelators with marked and selective antitumor activity: in vitro and in vivo assessment.Blood. 2004; 104: 1450-1458Crossref PubMed Scopus (341) Google Scholar). Its in vivo effects were consistent with it binding iron in the tumor and forming an intracellular iron complex that sequestered or redistributed iron away from the cellular iron-sensing mechanisms, resulting in up-regulation of genes classically increased during iron depletion i.e. TfR1 and VEGF1 (25.Dixon K.M. Lui G.Y. Kovacevic Z. Zhang D. Yao M. Chen Z. Dong Q. Assinder S.J. Richardson D.R. Dp44mT targets the AKT, TGF-β and ERK pathways via the metastasis suppressor NDRG1 in normal prostate epithelial cells and prostate cancer cells.Br. J. Cancer. 2013; 108: 409-419Crossref PubMed Scopus (88) Google Scholar). Furthermore, because of the treatment of mice with this novel chelator, there were higher iron levels in the liver, which corresponded with down-regulation of NDRG1 and also TfR1 and VEGF1 (26.Whitnall M. Howard J. Ponka P. Richardson D.R. A class of iron chelators with a wide spectrum of potent antitumor activity that overcomes resistance to chemotherapeutics.Proc. Natl. Acad. Sci. U.S.A. 2006; 103: 14901-14906Crossref PubMed Scopus (425) Google Scholar). This effect of increasing liver iron levels was a specific property of Dp44mT and also a related thiosemicarbazone, Triapine® (25.Dixon K.M. Lui G.Y. Kovacevic Z. Zhang D. Yao M. Chen Z. Dong Q. Assinder S.J. Richardson D.R. Dp44mT targets the AKT, TGF-β and ERK pathways via the metastasis suppressor NDRG1 in normal prostate epithelial cells and prostate cancer cells.Br. J. Cancer. 2013; 108: 409-419Crossref PubMed Scopus (88) Google Scholar), and it proved useful in demonstrating that NDRG1 was regulated by iron levels in vivo. Hence, the regulation of NDRG1 in vivo mirrors the regulation by iron observed in vitro in multiple studies performed by various independent investigators using many different protocols of iron depletion (9.Kovacevic Z. Fu D. Richardson D.R. The iron-regulated metastasis suppressor, Ndrg-1: Identification of novel molecular targets.Biochim. Biophys. Acta. 2008; 1783: 1981-1992Crossref PubMed Scopus (66) Google Scholar, 13.Kovacevic Z. Chikhani S. Lui G.Y. Sivagurunathan S. Richardson D.R. The iron-regulated metastasis suppressor NDRG1 targets NEDD4L, PTEN, and SMAD4 and inhibits the PI3K and Ras signaling pathways.Antioxid. Redox Signal. 2013; 18: 874-887Crossref PubMed Scopus (127) Google Scholar, 15.Liu W. Yue F. Zheng M. Merlot A. Bae D.H. Huang M. Lane D. Jansson P. Lui G.Y. Richardson V. Sahni S. Kalinowski D. Kovacevic Z. Richardson D.R. The proto-oncogene c-Src and its downstream signaling pathways are inhibited by the metastasis suppressor, NDRG1.Oncotarget. 2015; 6: 8851-8874Crossref PubMed Scopus (59) Google Scholar, 16.Wangpu X. Lu J. Xi R. Yue F. Sahni S. Park K.C. Menezes S. Huang M.L. Zheng M. Kovacevic Z. Richardson D.R. 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; 89: 521-540Crossref PubMed Scopus (42) Google Scholar, 21.Le N.T. Richardson D.R. Iron chelators with high antiproliferative activity up-regulate the expression of a growth inhibitory and metastasis suppressor gene: a link between iron metabolism and proliferation.Blood. 2004; 104: 2967-2975Crossref PubMed Scopus (257) Google Scholar, 22.Lane D.J. Saletta F. Suryo Rahmanto Y. Kovacevic Z. Richardson D.R. N-myc downstream regulated 1 (NDRG1) is regulated by eukaryotic initiation factor 3a (eIF3a) during cellular stress caused by iron depletion.PLoS ONE. 2013; 8: e57273Crossref PubMed Scopus (53) Google Scholar, 23.Chen Z. Zhang D. Yue F. Zheng M. Kovacevic Z. Richardson D.R. The iron chelators Dp44mT and DFO inhibit TGF-β-induced epithelial-mesenchymal transition via up-regulation of N-Myc downstream-regulated gene 1 (NDRG1).J. Biol. Chem. 2012; 287: 17016-17028Abstract Full Text Full Text PDF PubMed Scopus (194) Google Scholar, 24.Sun J. Zhang D. Zheng Y. Zhao Q. Zheng M. Kovacevic Z. Richardson D.R. Targeting the metastasis suppressor, NDRG1, using novel iron chelators: regulation of stress fiber-mediated tumor cell migration via modulation of the ROCK1/pMLC2 signaling pathway.Mol. Pharmacol. 2013; 83: 454-469Crossref PubMed Scopus (82) Google Scholar, 25.Dixon K.M. Lui G.Y. Kovacevic Z. Zhang D. Yao M. Chen Z. Dong Q. Assinder S.J. Richardson D.R. Dp44mT targets the AKT, TGF-β and ERK pathways via the metastasis suppressor NDRG1 in normal prostate epithelial cells and prostate cancer cells.Br. J. Cancer. 2013; 108: 409-419Crossref PubMed Scopus (88) Google Scholar, 26.Whitnall M. Howard J. Ponka P. Richardson D.R. A class of iron chelators with a wide spectrum of potent antitumor activity that overcomes resistance to chemotherapeutics.Proc. Natl. Acad. Sci. U.S.A. 2006; 103: 14901-14906Crossref PubMed Scopus (425) Google Scholar, 27.Saletta F. Suryo Rahmanto Y. Noulsri E. Richardson D.R. Iron chelator-mediated alterations in gene expression: identification of novel iron-regulated molecules that are molecular targets of hypoxia-inducible factor-1α and p53.Mol. Pharmacol. 2010; 77: 443-458Crossref PubMed Scopus (62) Google Scholar, 28.Kovacevic Z. Chikhani S. Lovejoy D.B. Richardson D.R. Novel thiosemicarbazone iron chelators induce up-regulation and phosphorylation of the metastasis suppressor N-myc downstream regulated gene 1: a new strategy for the treatment of pancreatic cancer.Mol. Pharmacol. 2011; 80: 598-609Crossref PubMed Scopus (145) Google Scholar, 29.Hickok J.R. Sahni S. Mikhed Y. Bonini M.G. Thomas D.D. Nitric oxide suppresses tumor cell migration through N-Myc Downstream-regulated Gene-1 (NDRG1) expression: role of chelatable iron.J. Biol. Chem. 2011; 286: 41413-41424Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar, 30.Salnikow K. Li X. Lippmann M. Effect of nickel and iron co-exposure on human lung cells.Toxicol. Appl. Pharmacol. 2004; 196: 258-265Crossref PubMed Scopus (43) Google Scholar, 31.Zhang P. Tchou-Wong K.M. Costa M. Egr-1 mediates hypoxia-inducible transcription of the NDRG1 gene through an overlapping Egr-1/Sp1 binding site in the promoter.Cancer Res. 2007; 67: 9125-9133Crossref PubMed Scopus (60) Google Scholar). Also consistent with this regulation are studies examining patients infected with hepatitis C virus, in which liver iron loading occurs, and NDRG1 is down-regulated (34.Hagist S. Sültmann H. Millonig G. Hebling U. Kieslich D. Kuner R. Balaguer S. Seitz H.K. Poustka A. Mueller S. In vitro-targeted gene identification in patients with hepatitis C using a genome-wide microarray technology.Hepatology. 2009; 49: 378-386Crossref PubMed Scopus (17) Google Scholar). In summary, studies in vitro and in vivo clearly demonstrate that NDRG1 is regulated by cellular iron depletion (32.Torti S.V. Torti F.M. Iron and cancer: more ore to be mined.Nat. Rev. Cancer. 2013; 13: 342-355Crossref PubMed Scopus (952) Google Scholar). It is noteworthy that whereas iron has been shown to regulate the expression of NDRG1, further studies are required to confirm whether this regulation of NDRG1 levels occur due to a direct response to changes in physiological iron availability. In terms of the iron-mediated regulation of NDRG1, studies by the authors first demonstrated that this occurred via both HIF-1α-independent and -dependent mechanisms (21.Le N.T. Richardson D.R. Iron chelators with high antiproliferative activity up-regulate the expression of a growth inhibitory and metastasis suppressor gene: a link between iron metabolism and proliferation.Blood. 2004; 104: 2967-2975Crossref PubMed Scopus (257) Google Scholar). This is important to consider because iron plays an important role in oncogenesis, due to its role in cell cycle progression, DNA synthesis, and proliferation (35.Nyholm S. Mann G.J. Johansson A.G. Bergeron R.J. Gräslund A. Thelander L. Role of ribonucleotide reductase in inhibition of mammalian-cell growth by potent iron chelators.J. Biol. Chem. 1993; 268: 26200-26205Abstract Full Text PDF PubMed Google Scholar, 36.Kalinowski D.S. Richardson D.R. The evolution of iron chelators for the treatment of iron overload disease and cancer.Pharmacol. Rev. 2005; 57: 547-583Crossref PubMed Scopus (616) Google Scholar). Of note, the iron chelators, desferrioxamine (DFO) and 2-hydroxyl-1-naphthaldehyde isonicotinoyl hydrazone (311), which cause cellular iron depletion and up-regulate HIF-1α, can then transactivate NDRG1 (21.Le N.T. Richardson D.R. Iron chelators with high antiproliferative activity up-regulate the expression of a growth inhibitory and metastasis suppressor gene: a link between iron metabolism and proliferation.Blood. 2004; 104: 2967-2975Crossref PubMed Scopus (257) Google Scholar). Additionally, the eukaryotic initiation factor, eIF3a, was also shown to positively regulate NDRG1 expression during iron depletion (22.Lane D.J. Saletta F. Suryo Rahmanto Y. Kovacevic Z. Richardson D.R. N-myc downstream regulated 1 (NDRG1) is regulated by eukaryotic initiation factor 3a (eIF3a) during cellular stress caused by iron depletion.PLoS ONE. 2013; 8: e57273Crossref PubMed Scopus (53) Google Scholar). This occurs through the induction and recruitment of eIF3a-positive stress granules that, during stressful conditions, cause NDRG1 mRNA and protein levels to increase (22.Lane D.J. Saletta F. Suryo Rahmanto Y. Kovacevic Z. Richardson D.R. N-myc downstream regulated 1 (NDRG1) is regulated by eukaryotic initiation factor 3a (eIF3a) during cellular stress caused by iron depletion.PLoS ONE. 2013; 8: e57273Crossref PubMed Scopus (53) Google Scholar). This was demonstrated to occur in the absence of HIF-1α expression and may constitute the HIF-1α-independent pathway of NDRG1 up-regulation after iron depletion (22.Lane D.J. Saletta F. Suryo Rahmanto Y. Kovacevic Z. Richardson D.R. N-myc downstream regulated 1 (NDRG1) is regulated by eukaryotic initiation factor 3a (eIF3a) during cellular stress caused by iron depletion.PLoS ONE. 2013; 8: e57273Crossref PubMed Scopus (53) Google Scholar). An additional HIF-1α-independent pathway has also been reported by Zhang et al. (31.Zhang P. Tchou-Won" @default.
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• W2625660736 date "2017-08-01" @default.
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