Abstract

One of the classic “hallmarks of cancer” is the ability for cancerous cells to activate invasion and metastasis, sustain proliferative signaling, and evade growth suppressors. Matrix-degrading enzymes such as cysteine cathepsin proteases are involved with cross talk between cancer cells and neighboring stroma, which are recruited for invasion. Cysteine cathepsins include a family of 11 cathepsins, some of which are the most powerful human collagenases and elastases and are active in acidic environments. Of particular interest are cathepsins K, L, and S, which share 60% sequence homology and redundancy in target substrate proteins with different catalytic activities toward different ECM substrates, which have been investigated in isolation. However, this is not physiologically relevant as cells secrete many proteases simultaneously in the body. Previously, it has been shown that one species of cathepsin will preferentially degrade another while also in the presence of matrix proteins; which is termed cathepsin cannibalism. This work uses a computational model to probe the proteolytic network of cathepsin cannibalism between multiple species and multiple substrates. Such networks are difficult to study experimentally in vitro, so computational modeling is essential in shedding light on this mechanism.