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  • The role of extracellular proteases in tumor progression and the development of innovative metal ion chelators that inhibit their activity

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    Dharmasivam443955-Published.pdf (1.638Mb)
    Author(s)
    Park, KC
    Dharmasivam, M
    Richardson, DR
    Griffith University Author(s)
    Richardson, Des R.
    Dharmasivam, Mahendiran
    Year published
    2020
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    Abstract
    The crucial role of extracellular proteases in cancer progression is well-known, especially in relation to the promotion of cell invasion through extracellular matrix remodeling. This also occurs by the ability of extracellular proteases to induce the shedding of transmembrane proteins at the plasma membrane surface or within extracellular vesicles. This process results in the regulation of key signaling pathways by the modulation of kinases, e.g., the epidermal growth factor receptor (EGFR). Considering their regulatory roles in cancer, therapeutics targeting various extracellular proteases have been discovered. These include ...
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    The crucial role of extracellular proteases in cancer progression is well-known, especially in relation to the promotion of cell invasion through extracellular matrix remodeling. This also occurs by the ability of extracellular proteases to induce the shedding of transmembrane proteins at the plasma membrane surface or within extracellular vesicles. This process results in the regulation of key signaling pathways by the modulation of kinases, e.g., the epidermal growth factor receptor (EGFR). Considering their regulatory roles in cancer, therapeutics targeting various extracellular proteases have been discovered. These include the metal-binding agents di-2-pyridylketone 4,4dimethyl-3-thiosemicarbazone (Dp44mT) and di-2-pyridylketone-4-cyclohexyl-4-methyl-3thiosemicarbazone (DpC), which increase c-MET degradation by multiple mechanisms. Both the direct and indirect inhibition of protease expression and activity can be achieved through metal ion depletion. Considering direct mechanisms, chelators can bind zinc(II) that plays a catalytic role in enzyme activity. In terms of indirect mechanisms, Dp44mT and DpC potently suppress the expression of the kallikrein-related peptidase—a prostate-specific antigen—in prostate cancer cells. The mechanism of this activity involves promotion of the degradation of the androgen receptor. Additional suppressive mechanisms of Dp44mT and DpC on matrix metalloproteases (MMPs) relate to their ability to up-regulate the metastasis suppressors N-myc downstream regulated gene1 (NDRG1) and NDRG2, which down-regulate MMPs that are crucial for cancer cell invasion.
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    Journal Title
    International Journal of Molecular Sciences
    Volume
    21
    Issue
    18
    DOI
    https://doi.org/10.3390/ijms21186805
    Copyright Statement
    © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
    Subject
    Other Chemical Sciences
    Genetics
    Other Biological Sciences
    Keywords: cancer therapeutics
    matrix metalloproteases
    prostate specific antigen
    thiosemicarbazones
    Publication URI
    http://hdl.handle.net/10072/397844
    Collection
    • Journal articles

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