Abstract
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.
Highlights
Extracellular proteases are essential in the regulation of myriads of physiological processes [1]
Some of the canonical roles of extracellular proteases have been known for many decades and include the digestion of consumed proteins by trypsin in the small intestine, while the relatively recent finding of proteases on the surface of exosomes further opens the door to understanding the complex biology of cell matrix remodeling by extracellular proteases [4]
More recently, studies have revealed that proteases have complex roles in cancer, such as the inhibition of receptor tyrosine kinase signaling mediated by ectodomain shedding [7]
Summary
Extracellular proteases are essential in the regulation of myriads of physiological processes [1]. Some of the canonical roles of extracellular proteases have been known for many decades and include the digestion of consumed proteins by trypsin in the small intestine, while the relatively recent finding of proteases on the surface of exosomes further opens the door to understanding the complex biology of cell matrix remodeling by extracellular proteases [4]. This review will discuss oncogenic functions that extracellular proteases mediate in cancer, as well as novel protease-targeting therapeutics currently in development. These include novel thiosemicarbazones from our laboratory [8,9,10]
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