Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0376358 (prostate cancer)
 59,338 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Unlike in normal epithelium, dysregulated overactivation of various proteases have been reported in cancers. Degradation of pericancerous extracellular matrix leading to cancer cell invasion by matrix metalloproteases is well known evidence. On the other hand, several cell-surface proteases, including type II transmembrane serine proteases (TTSPs), also induce progression through activation of growth factors, protease activating receptors and other proteases. Hepatocyte growth factor (HGF) known as a multifunctional growth factor that upregulates cancer cell motility, invasiveness, proliferative, and anti-apoptotic activities through phosphorylation of MET (a specific receptor of HGF). HGF secreted as inactive zymogen (pro-HGF) from cancer associated stromal fibroblasts, and the proteolytic activation by several TTSPs including matriptase and hepsin is required. The activation is strictly regulated by HGF activator inhibitors (HAIs) in physiological condition. However, downregulation is frequently observed in cancers. Indeed, overactivation of MET by upregulation of matriptase and hepsin accompanied by the downregulation of HAIs in urological cancers (prostate cancer, renal cell carcinoma, and bladder cancer) are also reported, a phenomenon observed in cancer cells with malignant phenotype, and correlated with poor prognosis. In this review, we summarized current reports focusing on TTSPs, HAIs, and MET signaling axis in urological cancers.
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PMID:Dysregulation of Type II Transmembrane Serine Proteases and Ligand-Dependent Activation of MET in Urological Cancers. 3229 Apr 2

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 4,4-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.
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PMID:The Role of Extracellular Proteases in Tumor Progression and the Development of Innovative Metal Ion Chelators that Inhibit their Activity. 3294 29

Protein tyrosine kinase 6 (PTK6) is the most well studied member of the PTK6 family of intracellular tyrosine kinases. While it is expressed at highest levels in differentiated cells in the regenerating epithelial linings of the gastrointestinal tract and skin, induction and activation of PTK6 is detected in several cancers, including breast and prostate cancer where high PTK6 expression correlates with worse outcome. PTK6 expression is regulated by hypoxia and cell stress, and its kinase activity is induced by several growth factor receptors implicated in cancer including members of the ERBB family, IGFR1 and MET. Activation of PTK6 at the plasma membrane has been associated with the epithelial mesenchymal transition and tumor metastasis. Several lines of evidence indicate that PTK6 has context dependent functions that depend on cell type, intracellular localization and kinase activation. Systemic disruption of PTK6 has been shown to reduce tumorigenesis in mouse models of breast and prostate cancer, and more recently small molecule inhibitors of PTK6 have exhibited efficacy in inhibiting tumor growth in animal models. Here we review data that suggest targeting PTK6 may have beneficial therapeutic outcomes in some cancers.
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PMID:Targeting protein tyrosine kinase 6 in cancer. 3295 64


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