Proteases in cancer-enzyme

Proteases in normal cells are important in carrying out biological processes. In living systems, a balance between proteases and their anti-proteases occur, and disturbance of balance leads to many diseases like cancer. Steps starting from tumor initiation, growth, metastasis and finally invasion into some other site involve all five classes of proteases: serine, cysteine, aspartate, threonine and matrix metalloproteases. A great number of reports have shown a correlation between the activity of lysosomal cysteine proteases and tumor progression.

Trypsin, one of the typical well-known digestive serine protease has also been found to be involved in various cancers and promotes proliferation, invasion and metastasis. The colorectal cancer with trypsin expression has poor prognosis and shorter disease free survival. Protease involvement in cancer suggests the use of protease inhibitors as anticancer drugs. In this review, we will focus on role of proteases in various processes of carcinogenesis and some protease inhibitor based drugs.

Mammalian cysteine proteases form a diverse group of proteolytic enzymes characterized by an active site cysteine residue. Cysteine proteases mediate general functions such as intracellular protein catabolism and specialized functions such as selective activation of signalling molecules (interleukin, enkephalin, protein kinase C) or extracellular protein degradation (bone resorption, macrophage function).

Serine proteases form a group of proteases which have close relationship with cell growth and differentiation. They often exist as zymogens and are activated by specific and limited proteolysis, which in turn regulate the enzyme activities. There also exist as physiological inhibitors inside cells, which regulate their activities. Normal regulation of serine protease activities is essential for physiological activities of the cell, and abnormal regulation of these protease activities can lead to pathological conditions. Urokinase-type plasminogen activators are one kind of serine proteases that have been well investigated for their relationship with tumor invasion and metastasis.

Aspartic proteases form a group of enzymes that consist of two lobes separated by a cleft containing the catalytic site made up of two aspartate residues. Cathepsin–D (Cath-D) is an aspartic endo-protease that is ubiquitously distributed in lysosomes The aspartic protease cathepsin D (cath-D), a marker of poor prognosis in breast cancer is overexpressed and secreted at high levels by human epithelial breast cancer cells.

Threonine proteases (proteasomes) have the task of eliminating cellular proteins, tagged for degradation through a complex modification termed polyubiquitinization. It is a process of addition of a series of ubiquitin molecules to another protein, targeted for degradation.

MMPs are responsible for the turnover and remodeling of extracellular matrix proteins. Substrates for the enzymes range from the fibrillar collagens of bone, skin and interstitial, to the non-fibrillar collagens, laminina. As might be expected for enzymes with such degradative potential, the activity of MMPs is highly controlled.