title: Nitric oxide suppresses tumor cell migration through N-Myc downstream-regulated gene-1 (NDRG1) expression: role of chelatable iron.
abstract: N-Myc downstream-regulated gene 1 (NDRG1) is a ubiquitous cellular protein that is up-regulated under a multitude of stress and growth-regulatory conditions. Although the exact cellular functions of this protein have not been elucidated, mutations in this gene or aberrant expression of this protein have been linked to both tumor suppressive and oncogenic phenotypes. Previous reports have demonstrated that NDRG1 is strongly up-regulated by chemical iron chelators and hypoxia, yet its regulation by the free radical nitric oxide ((•)NO) has never been demonstrated. Herein, we examine the chemical biology that confers NDRG1 responsiveness at the mRNA and protein levels to (•)NO. We demonstrate that the interaction of (•)NO with the chelatable iron pool (CIP) and the appearance of dinitrosyliron complexes (DNIC) are key determinants. Using HCC 1806 triple negative breast cancer cells, we find that NDRG1 is up-regulated by physiological (•)NO concentrations in a dose- and time-dependant manner. Tumor cell migration was suppressed by NDRG1 expression and we excluded the involvement of HIF-1α, sGC, N-Myc, and c-Myc as upstream regulatory targets of (•)NO. Augmenting the chelatable iron pool abolished (•)NO-mediated NDRG1 expression and the associated phenotypic effects. These data, in summary, reveal a link between (•)NO, chelatable iron, and regulation of NDRG1 expression and signaling in tumor cells.
authors: Departments of Medicinal Chemistry and Pharmacognosy, University of Illinois, Chicago, Illinois 60612.
authors: Jason R
authors: JR
authors: Hickok
authors: Departments of Medicinal Chemistry and Pharmacognosy, University of Illinois, Chicago, Illinois 60612.
authors: Sumit
authors: S
authors: Sahni
authors: Departments of Medicinal Chemistry and Pharmacognosy, University of Illinois, Chicago, Illinois 60612.
authors: Yuliya
authors: Y
authors: Mikhed
authors: Departments of Medicine and Pharmacology, University of Illinois, Chicago, Illinois 60612.
authors: Marcelo G
authors: MG
authors: Bonini
authors: Departments of Medicinal Chemistry and Pharmacognosy, University of Illinois, Chicago, Illinois 60612. Electronic address: ddthomas@uic.edu.
authors: Douglas D
authors: DD
authors: Thomas
mesh_terms: D001943:Breast Neoplasms; D018797:Cell Cycle Proteins / Q000096:biosynthesis*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D005260:Female; D016166:Free Radical Scavengers / Q000378:metabolism / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D007501:Iron / Q000378:metabolism / Q000494:pharmacology*; D009569:Nitric Oxide / Q000378:metabolism / Q000494:pharmacology*; D009589:Nitrogen Oxides / Q000378:metabolism / Q000494:pharmacology*; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D000099259:N-myc Downstream-Regulated Gene 1 Protein
chemical_list: D018797:Cell Cycle Proteins; D016166:Free Radical Scavengers; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D047908:Intracellular Signaling Peptides and Proteins; D007501:Iron; D009569:Nitric Oxide; D009589:Nitrogen Oxides; D016271:Proto-Oncogene Proteins c-myc; D000099259:N-myc Downstream-Regulated Gene 1 Protein; C497442:HIF1A protein, human; C489427:MYC protein, human; C073661:dinitrosyl iron complex