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Iron Chelation In Cancer Metastasis Supression

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  1. #1
    ironjustice Guest

    Default Iron Chelation In Cancer Metastasis Supression

    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
    Jing Sun, Daohai Zhang, Ying Zheng, Qian Zhao, Minhua Zheng, Zaklina
    Kovacevic, and Des R. Richardson
    Department of General Surgery, Ruijin Hospital,
    Shanghai Jiao Tong University School of Medicine, Shanghai, P.R.China
    (J.S., M.Z.); Department of Pathology, University of Sydney, New South
    Wales, Australia (D.Z., Z.K., D.R.R.); and Department of
    Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis
    of Chinese Ministry of Education, Shanghai Jiao Tong University School
    of Medicine, Shanghai, P.R. China (Y.Z., Q.Z.)
    Address correspondence to:
    Dr. D. R. Richardson, Iron Metabolism and Chelation Program,
    Department of Pathology and Bosch Institute, University of Sydney,
    Sydney, New South Wales, 2006 Australia.
    E-mail: [email protected]
    J.S. and D.Z. contributed equally as first authors. M.Z., Z.K. and
    D.R.R. contributed equally as co-corresponding authors.

    Abstract
    The iron-regulated metastasis suppressor, N-myc downstream-regulated
    gene 1 (NDRG1), is up-regulated by cellular iron depletion mediated by
    iron chelators and can inhibit cancer cell migration.
    However, the mechanism of how NDRG1 achieves this effect remains
    unclear.
    In this study, we implemented established and newly constructed NDRG1
    overexpression and knockdown models using the DU145, HT29, and HCT116
    cancer cell lines to investigate the molecular basis by which NDRG1
    exerts its inhibitory effect on cell migration.
    Using these models, we demonstrated that NDRG1 overexpression inhibits
    cell migration by preventing actin-filament polymerization, stress
    fiber assembly and formation. In contrast, NDRG1 knockdown had the
    opposite effect. Moreover, we identified that NDRG1 inhibited an
    important regulatory pathway mediated by the Rho-associated, coiled-
    coil containing protein kinase 1 (ROCK1)/phosphorylated myosin light
    chain 2 (pMLC2) pathway that modulates stress fiber assembly. The
    phosphorylation of MLC2 is a key process in inducing stress fiber
    contraction, and this was shown to be markedly decreased or increased
    by NDRG1 overexpression or knockdown, respectively. The mechanism
    involved in the inhibition of MLC2 phosphorylation by NDRG1 was
    mediated by a significant (P < 0.001) decrease in ROCK1 expression
    that is a key kinase involved in MLC2 phosphorylation. Considering
    that NDRG1 is up-regulated after cellular iron depletion, novel
    thiosemicarbazone iron chelators (e.g., di-2-pyridylketone 4,4-
    dimethyl-3-thiosemicarbazone) were demonstrated to inhibit ROCK1/pMLC2-
    modulated actin-filament polymerization, stress fiber assembly, and
    formation via a mechanism involving NDRG1. These results highlight the
    role of the ROCK1/pMLC2 pathway in the NDRG1-mediated antimetastatic
    signaling network and the therapeutic potential of iron chelators at
    inhibiting metastasis.

    Footnotes
    The work was supported by the National Health and Medical Research
    Council of Australia [Project Grant 632778, Senior Principal Research
    Fellowship 571123, Early Career Fellowship 1037323] and the National
    Natural Science Foundation of China [Grants 30971488 and 81172521].
    The authors declare no conflict of interest.
    dx.doi.org/10.1124/mol.112.083097.
    ↵This article has supplemental material available at
    molpharm.aspetjournals.org.
    Received October 21, 2012.
    Accepted November 27, 2012.
    Copyright В© 2013 by The American Society for Pharmacology and
    Experimental Therapeutics


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  2. #2
    ironjustice Guest

    Default Re: Iron Chelation In Cancer Metastasis Supression

    On Jan 18, 3:39В*pm, ironjustice <ironjust...@rock.com> wrote:
    Targeting the Metastasis Suppressor, NDRG1, Using Novel Iron Chelators
    <<

    "IP6 exerts its anti-metastatic activity"

    The effect of inositol hexaphosphate on the expression of selected
    metalloproteinases and their tissue inhibitors in IL-1ОІ-stimulated
    colon cancer cells.
    Kapral M, Wawszczyk J, Jurzak M, Hollek A, WД™glarz L.
    Int J Colorectal Dis. 2012 Nov;27(11):1419-28.
    Department of Biochemistry, Medical University of Silesia, 41-200
    Sosnowiec, Narcyzow 1, Poland. [email protected]

    Abstract
    INTRODUCTION: Matrix metalloproteinases (MMPs) have repeatedly been
    shown to play a very active role in extracellular matrix degradation
    associated with tumor invasion and metastasis.
    Tissue inhibitors of MMPs (TIMPs) are well-known for their ability to
    inhibit MMP activity thereby inhibiting malignant progression.
    Inositol hexaphosphate (IP6 phytic acid) has been recognized to have
    both preventive and therapeutic effects against various cancers
    including that of colon.
    In in vitro studies, IP6 has been demonstrated to inhibit cancer cell
    adhesion and migration.
    In the present study, the effect of IP6 on the expression of MMP and
    TIMP genes was evaluated in unstimulated and IL-1ОІ-stimulated colon
    cancer cell line Caco-2.

    MATERIALS AND METHODS: Real-time QRT-PCR was used to validate the
    transcription level of selected MMP and TIMP genes in Caco-2 cells
    after treatment with 1 ng/ml of IL-1ОІ, 2.5 mM of IP6, and both for 6,
    12, and 24 h.

    RESULTS: Stimulation of cells with IL-1ОІ only resulted in an
    overexpression of MMP and their TIMP mRNAs.
    A significant decrease in MMP-13, MMP-3, MMP-2, and TIMP-1 basal
    expression was achieved by IP6.
    IP6 was also an efficient downregulator of MMP-1, MMP-9, and TIMP-2
    genes transcription stimulated by IL-1ОІ in 6 h lasting culture.
    After 12 h, IL-1ОІ-induced MMP-2 mRNA expression was significantly
    reduced by IP6.

    CONCLUSION: Proinflammatory cytokine IL-1ОІ upregulates MMP and TIMP
    mRNAs expression in colon cancer epithelial cells Caco-2.
    IP6 (2.5 mM) influences constitutive expression of both MMP and TIMP
    genes and downregulates IL-1ОІ stimulated transcription of some of
    these genes.
    IP6 exerts its anti-metastatic activity through modulation of MMP and
    TIMP genes expression to prevent cancer cell migration and invasion.

    PMID:22415590

    doi: 10.1007/s00384-012-1445-3.

    ------------------

    "Natural iron chelator, phytic acid"

    http://www.ncbi.nlm.nih.gov/pubmed/18255213

    Who loves ya.
    Tom


    Jesus Was A Vegetarian!
    http://tinyurl.com/2r2nkh


    Man Is A Herbivore!
    http://tinyurl.com/4rq595


    DEAD PEOPLE WALKING
    http://tinyurl.com/zk9fk


    > 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
    > Jing Sun, Daohai Zhang, Ying Zheng, Qian Zhao, Minhua Zheng, Zaklina
    > Kovacevic, and Des R. Richardson
    > Department of General Surgery, Ruijin Hospital,
    > Shanghai Jiao Tong University School of Medicine, Shanghai, P.R.China
    > (J.S., M.Z.); Department of Pathology, University of Sydney, New South
    > Wales, Australia (D.Z., Z.K., D.R.R.); and Department of
    > Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis
    > of Chinese Ministry of Education, Shanghai Jiao Tong University School
    > of Medicine, Shanghai, P.R. China (Y.Z., Q.Z.)
    > Address correspondence to:
    > Dr. D. R. Richardson, Iron Metabolism and Chelation Program,
    > Department of Pathology and Bosch Institute, University of Sydney,
    > Sydney, New South Wales, 2006 Australia.
    > E-mail: d.richard...@med.usyd.edu.au
    > J.S. and D.Z. contributed equally as first authors. M.Z., Z.K. and
    > D.R.R. contributed equally as co-corresponding authors.
    >
    > Abstract
    > The iron-regulated metastasis suppressor, N-myc downstream-regulated
    > gene 1 (NDRG1), is up-regulated by cellular iron depletion mediated by
    > iron chelators and can inhibit cancer cell migration.
    > However, the mechanism of how NDRG1 achieves this effect remains
    > unclear.
    > In this study, we implemented established and newly constructed NDRG1
    > overexpression and knockdown models using the DU145, HT29, and HCT116
    > cancer cell lines to investigate the molecular basis by which NDRG1
    > exerts its inhibitory effect on cell migration.
    > Using these models, we demonstrated that NDRG1 overexpression inhibits
    > cell migration by preventing actin-filament polymerization, stress
    > fiber assembly and formation. In contrast, NDRG1 knockdown had the
    > opposite effect. Moreover, we identified that NDRG1 inhibited an
    > important regulatory pathway mediated by the Rho-associated, coiled-
    > coil containing protein kinase 1 (ROCK1)/phosphorylated myosin light
    > chain 2 (pMLC2) pathway that modulates stress fiber assembly. The
    > phosphorylation of MLC2 is a key process in inducing stress fiber
    > contraction, and this was shown to be markedly decreased or increased
    > by NDRG1 overexpression or knockdown, respectively. The mechanism
    > involved in the inhibition of MLC2 phosphorylation by NDRG1 was
    > mediated by a significant (P < 0.001) decrease in ROCK1 expression
    > that is a key kinase involved in MLC2 phosphorylation. Considering
    > that NDRG1 is up-regulated after cellular iron depletion, novel
    > thiosemicarbazone iron chelators (e.g., di-2-pyridylketone 4,4-
    > dimethyl-3-thiosemicarbazone) were demonstrated to inhibit ROCK1/pMLC2-
    > modulated actin-filament polymerization, stress fiber assembly, and
    > formation via a mechanism involving NDRG1. These results highlight the
    > role of the ROCK1/pMLC2 pathway in the NDRG1-mediated antimetastatic
    > signaling network and the therapeutic potential of iron chelators at
    > inhibiting metastasis.
    >
    > Footnotes
    > The work was supported by the National Health and Medical Research
    > Council of Australia [Project Grant 632778, Senior Principal Research
    > Fellowship 571123, Early Career Fellowship 1037323] and the National
    > Natural Science Foundation of China [Grants 30971488 and 81172521].
    > The authors declare no conflict of interest.
    > dx.doi.org/10.1124/mol.112.083097.
    > ↵This article has supplemental material available at
    > molpharm.aspetjournals.org.
    > Received October 21, 2012.
    > Accepted November 27, 2012.
    > Copyright В© 2013 by The American Society for Pharmacology and
    > Experimental Therapeutics
    >
    > Who loves ya.
    > Tom
    >
    > Jesus Was A Vegetarian!http://tinyurl.com/2r2nkh
    >
    > Man Is A Herbivore!http://tinyurl.com/4rq595
    >
    > DEAD PEOPLE WALKINGhttp://tinyurl.com/zk9fk



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