title: Molecular functions of the iron-regulated metastasis suppressor, NDRG1, and its potential as a molecular target for cancer therapy.
abstract: N-myc down-regulated gene 1 (NDRG1) is a known metastasis suppressor in multiple cancers, being also involved in embryogenesis and development, cell growth and differentiation, lipid biosynthesis and myelination, stress responses and immunity. In addition to its primary role as a metastasis suppressor, NDRG1 can also influence other stages of carcinogenesis, namely angiogenesis and primary tumour growth. NDRG1 is regulated by multiple effectors in normal and neoplastic cells, including N-myc, histone acetylation, hypoxia, cellular iron levels and intracellular calcium. Further, studies have found that NDRG1 is up-regulated in neoplastic cells after treatment with novel iron chelators, which are a promising therapy for effective cancer management. Although the pathways by which NDRG1 exerts its functions in cancers have been documented, the relationship between the molecular structure of this protein and its functions remains unclear. In fact, recent studies suggest that, in certain cancers, NDRG1 is post-translationally modified, possibly by the activity of endogenous trypsins, leading to a subsequent alteration in its metastasis suppressor activity. This review describes the role of this important metastasis suppressor and discusses interesting unresolved issues regarding this protein.
authors.affiliation: Molecular Pharmacology and Pathology Program, Discipline of Pathology and Bosch Institute, Blackburn Building (D06), The University of Sydney, Sydney, NSW 2006, Australia.
authors.forename: Bernard A
authors.initials: BA
authors.lastname: Fang
authors.affiliation: Molecular Pharmacology and Pathology Program, Discipline of Pathology and Bosch Institute, Blackburn Building (D06), The University of Sydney, Sydney, NSW 2006, Australia.
authors.forename: Žaklina
authors.initials: Ž
authors.lastname: Kovačević
authors.affiliation: Molecular Pharmacology and Pathology Program, Discipline of Pathology and Bosch Institute, Blackburn Building (D06), The University of Sydney, Sydney, NSW 2006, Australia.
authors.forename: Kyung Chan
authors.initials: KC
authors.lastname: Park
authors.affiliation: Molecular Pharmacology and Pathology Program, Discipline of Pathology and Bosch Institute, Blackburn Building (D06), The University of Sydney, Sydney, NSW 2006, Australia.
authors.forename: Danuta S
authors.initials: DS
authors.lastname: Kalinowski
authors.affiliation: Molecular Pharmacology and Pathology Program, Discipline of Pathology and Bosch Institute, Blackburn Building (D06), The University of Sydney, Sydney, NSW 2006, Australia.
authors.forename: Patric J
authors.initials: PJ
authors.lastname: Jansson
authors.affiliation: Molecular Pharmacology and Pathology Program, Discipline of Pathology and Bosch Institute, Blackburn Building (D06), The University of Sydney, Sydney, NSW 2006, Australia.
authors.forename: Darius J R
authors.initials: DJ
authors.lastname: Lane
authors.affiliation: Molecular Pharmacology and Pathology Program, Discipline of Pathology and Bosch Institute, Blackburn Building (D06), The University of Sydney, Sydney, NSW 2006, Australia.
authors.forename: Sumit
authors.initials: S
authors.lastname: Sahni
authors.affiliation: Molecular Pharmacology and Pathology Program, Discipline of Pathology and Bosch Institute, Blackburn Building (D06), The University of Sydney, Sydney, NSW 2006, Australia. Electronic address: d.richardson@med.usyd.edu.au.
authors.forename: Des R
authors.initials: DR
authors.lastname: Richardson
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D018797:Cell Cycle Proteins / Q000032:analysis / Q000737:chemistry / Q000502:physiology*; D002454:Cell Differentiation; D047108:Embryonic Development; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000032:analysis / Q000737:chemistry / Q000502:physiology*; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000628:therapy*; D017434:Protein Structure, Tertiary; D014357:Trypsin / Q000502:physiology; D025521:Tumor Suppressor Proteins / Q000502:physiology*; D000099259:N-myc Downstream-Regulated Gene 1 Protein
chemical_list: D018797:Cell Cycle Proteins; D047908:Intracellular Signaling Peptides and Proteins; D014357:Trypsin; D025521:Tumor Suppressor Proteins; D000099259:N-myc Downstream-Regulated Gene 1 Protein
keywords: 2-hydroxy-1-naphthaldehyde isonicotinoyl hydrazone; 70-kDa heat shock cognate protein; Akt; CMT4D; CPT-11; Charcot–Marie–Tooth disease, type 4D; DFO; Dp44mT; DpC; DpT; ECM; EGR1; ERG-1; ETS; HDL-C; HIF-1α; HMSNL; HTE; HUVEC; Hsc70; IL; LDL; LPC; MMP; Metastasis suppressor; N-myc down-regulated gene 1; N-myc down-stream regulated gene 1; NDRG1; NF-κB; NIH; PAR-1; PKA; PTEN; PrEC; ROCK1; ROS; Rho-associated, coiled-coil containing protein kinase 1 (ROCK1); SGK; T-cell factor/lymphoid enhancer-binding factor; TAT; TAT2; TCF/LEF; Thiosemicarbazone; Thtpa; VEGF; deferoxamine (or desferrioxamine B); di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone; di-2-pyridylketone 4-cyclohexyl-4-methyl-3-thiosemicarbazone; di-2-pyridylketone thiosemicarbazone; early growth factor-1; extracellular matrix; hereditary motor and sensory neuropathy-Lom; high-density lipoprotein cholesterol; human tracheal epithelial cell; human umbilical vein endothelial cell; hypoxia inducible factor-1α; interleukin; irinotecan; low-density lipoprotein; lysophosphatidylcholine; matrix metalloproteinase; nuclear factor-κB; pMLC2; pVHL; phosphatase and tensin homologue deleted on chromosome 10; phosphorylated myosin light chain 2; prostate epithelial cell; protease activated receptor; protein kinase A; protein kinase B; protein kinase C; reactive oxygen species; serum- and glucocorticoid-induced kinase; thiamine triphosphatase; tumour-associated trypsinogen; tumour-associated trypsinogen-2; v-ets avian erythroblastosis virus E26 oncogene homologue; v-ets avian erythroblastosis virus E26 oncogene homologue 2; vascular endothelial growth factor; von Hippel–Lindau protein