The Role of Extracellular Proteases in Tumor Progression and the Development of Innovative Metal Ion Chelators That Inhibit Their Activity
The 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 membran...
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MDPI AG
2020-09-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/21/18/6805 |
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| author | Kyung Chan Park Mahendiran Dharmasivam Des R. Richardson |
| author_facet | Kyung Chan Park Mahendiran Dharmasivam Des R. Richardson |
| author_sort | Kyung Chan Park |
| collection | DOAJ |
| description | The 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 4,4-dimethyl-3-thiosemicarbazone (Dp44mT) and di-2-pyridylketone-4-cyclohexyl-4-methyl-3-thiosemicarbazone (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 gene-1 (NDRG1) and NDRG2, which down-regulate MMPs that are crucial for cancer cell invasion. |
| first_indexed | 2024-03-10T16:16:59Z |
| format | Article |
| id | doaj.art-888de1cf763a4b9e9ffa144b0f61ffdd |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T16:16:59Z |
| publishDate | 2020-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-888de1cf763a4b9e9ffa144b0f61ffdd2023-11-20T13:58:40ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672020-09-012118680510.3390/ijms21186805The Role of Extracellular Proteases in Tumor Progression and the Development of Innovative Metal Ion Chelators That Inhibit Their ActivityKyung Chan Park0Mahendiran Dharmasivam1Des R. Richardson2Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, Medical Foundation Building, University of Sydney, Sydney 2006, AustraliaMolecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, Medical Foundation Building, University of Sydney, Sydney 2006, AustraliaMolecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, Medical Foundation Building, University of Sydney, Sydney 2006, AustraliaThe 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 4,4-dimethyl-3-thiosemicarbazone (Dp44mT) and di-2-pyridylketone-4-cyclohexyl-4-methyl-3-thiosemicarbazone (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 gene-1 (NDRG1) and NDRG2, which down-regulate MMPs that are crucial for cancer cell invasion.https://www.mdpi.com/1422-0067/21/18/6805cancer therapeuticsthiosemicarbazonesprostate specific antigenmatrix metalloproteases |
| spellingShingle | Kyung Chan Park Mahendiran Dharmasivam Des R. Richardson The Role of Extracellular Proteases in Tumor Progression and the Development of Innovative Metal Ion Chelators That Inhibit Their Activity International Journal of Molecular Sciences cancer therapeutics thiosemicarbazones prostate specific antigen matrix metalloproteases |
| title | The Role of Extracellular Proteases in Tumor Progression and the Development of Innovative Metal Ion Chelators That Inhibit Their Activity |
| title_full | The Role of Extracellular Proteases in Tumor Progression and the Development of Innovative Metal Ion Chelators That Inhibit Their Activity |
| title_fullStr | The Role of Extracellular Proteases in Tumor Progression and the Development of Innovative Metal Ion Chelators That Inhibit Their Activity |
| title_full_unstemmed | The Role of Extracellular Proteases in Tumor Progression and the Development of Innovative Metal Ion Chelators That Inhibit Their Activity |
| title_short | The Role of Extracellular Proteases in Tumor Progression and the Development of Innovative Metal Ion Chelators That Inhibit Their Activity |
| title_sort | role of extracellular proteases in tumor progression and the development of innovative metal ion chelators that inhibit their activity |
| topic | cancer therapeutics thiosemicarbazones prostate specific antigen matrix metalloproteases |
| url | https://www.mdpi.com/1422-0067/21/18/6805 |
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