Pharmacological Protease Inhibitor Preserves Proteolytic Activity In Breast Cancer Cells: Computational Models To Probe Unexpected Cellular Responses

• DOI: 10.1096/fasebj.2018.32.1_supplement.895.1
• Publication Date: 2021-06-07T11:37:36Z
• Authors: William Andrew Sh...; Chris Kieslich; Catera Wilder; Ken Brandon; Manu Platt
• Keywords: Cathepsin S; Cathepsin L1; Cathepsin A

Cysteine cathepsins are powerful elastases and collagenases, produced by breast cancer cells tumor associated macrophages, capable of remodeling extracellular matrix driving growth metastasis. Cathepsin expression activity regulated endogenous protein inhibitors as well proteolytic interactive networks that not completely understood. To date, no cathepsin have cleared clinical trials due to side effects including increased stroke risk. Surprisingly, inhibitor treatment has been with activity. This unexpected increase in could be contributing observed effects, but mechanisms responsible for this identified. Furthermore, following is consistent across different members the family. We previously published MDA‐MB‐231 treated pharmacological E64 active S decreased L, despite change total detectable or mRNA. Subsequent experiments revealed similar responses other macrophage cell lines, suggesting response a biological phenomenon, which if elucidated would inform cancer. The objective work use mathematical modeling test multiple explaining specific changes treatment. A series models were developed R potential hypothesized enzyme consist ordinary differential equations based on principles generalized mass action, simulating production, activation, inhibition degradation L cells. model architecture allows us investigate regulatory nodes “life‐cycle”. can degrade cathepsins, phenomenon we termed cannibalism. Our first tested hypothesis was inhibiting preventing it from degrading S. However, able recapitulate experimental results. next stabilizing S, increasing its over time. found formation stable complexes explain activity, while loss explained disrupting binding intracellular substrates inhibitors. also predicted production significantly greater than supported experimentally using translational cycloheximide, turnover proceeds more quickly Taken together, these results suggest protease cause both accumulation proteases depletion proteases, appreciable protein. important design successful application future prevent off‐target trial ending effects. Support Funding Information funded NSF CBET‐0939511. abstract Experimental Biology 2018 Meeting. There full text article FASEB Journal .