Abstract
In keeping with recent developments in basic research; the importance of the Cathepsins as targets in cancer therapy have taken on increasing importance and given rise to a number of key areas of interest in the clinical setting. In keeping with driving basic research in this area in a translational direction; recent findings have given rise to a number of exciting developments in the areas of cancer diagnosis; prognosis and therapeutic development. As a fast-moving area of research; the focus of this review brings together the latest findings and highlights the translational significance of these developments.
Highlights
Taken with the observations that some of these proteases are found to show upregulated levels of expression in cancer progression, it comes as no surprise that some of them have been validated as potential therapeutic targets in normal developing cancer types and cancer types that show resistance to regular chemotherapeutic regimes
As the expression of certain cathepsins are significantly upregulated in certain cancer types it has been reported that their ablation has the potential to sensitize cancer cells to conventional chemotherapeutic treatments
The cathepsin family range in 50 to 90 KDa in size which after translation are inserted into the endoplasmic reticulum (ER), where they enter the secretory pathway as inactive zymogens
Summary
The cathepsin family of proteases have gained significant attention in the field of cancer biology due to their ability to modulate the architecture of the Extracellular Matrix (ECM, promoting tumor dispersal) [1,2]. When taken with the observations that some members of this family of 15 proteases show pleiotropic activity towards common substrates [8], it does make the task of designing therapeutics against cancer-specific cathepsins more arduous that expected. All cysteine cathepsins can be regulated by the naturally-occurring endogenous cystatin inhibitors (Figure 1A) This key step may modulate the invasiveness of cells aberrantly expressing the cathepsin proteins [19]. Cystatins have been classified based upon subfamilies and family members of Clan IH (see Figure 1B) How these inhibitor proteins exert their activity in disease through the modulation of specific cysteine cathepsins (Table 1) has been evidenced over the recent years through structural studies and has generated a great deal of therapeutic interest [21]. We evaluate recent advancements in the use of these various approaches and the potential they hold in quantifying active cathepsin proteases for diagnostic, prognostic and therapeutic purposes
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