Abstract
Calpain‐2 levels are higher in colorectal tumors resistant to chemotherapy and previous work showed calpain‐2 inhibitor therapy reduced inflammation‐driven colorectal cancer, but direct effects of the inhibitor on colon cancer cells themselves were not demonstrated. In the present study, five human colon cancer cell lines were directly treated with a calpain‐2 inhibitor and results showed increased cell death in 4 of 5 cell lines and decreased anchorage‐independent growth for all cell five lines. When tested for levels of calpain‐2, three cell lines exhibited increasing levels of this enzyme: HCT15 (low), HCC2998 (medium), and HCT116 (significantly higher). This was consistent with gel shift assays showing that calpain‐2 inhibitor reduced of NF‐κB nuclear translocation most effectively in HCT116 cells. Ability of calpain‐2 inhibitor to impede tumor progression in vivo was evaluated using intrarectal transplant of luciferase‐expressing cells for these three cell lines. Results showed that calpain‐2 inhibitor therapy reduced tumor growth and increased survival only in mice injected with HCT116 cells. These data suggest calpain‐2 inhibitor treatment may be most effective on colorectal tumors expressing highest levels of calpain‐2.
Highlights
Calpains are calcium-dependent cysteine proteases that regulate a wide variety of cellular activities [1]
We evaluated a panel of NCI-60 human colon cancer cell lines treated with vehicle control (DMSO) or calpain-2 inhibitor using propidium iodide staining and soft agar colony assays
With the development of precision medicine, it is likely that information gathered on patient biopsy or resection samples will need to be utilized for guiding decisions on how responsive colon cancer cases will be to calpain-2 inhibitors
Summary
Calpains are calcium-dependent cysteine proteases that regulate a wide variety of cellular activities [1]. Calpains cleave their targets between functional domains, thereby altering the signaling or functions of the cleaved domains. There are 15 calpain isoforms, with calpain-1 and calpain-2 being the most ubiquitously expressed [2]. The activity of these enzymes is regulated by calcium binding, but by other factors including subcellular localization, membrane association, and actions of the endogenous inhibitor calpastatin [3]. Excessive calpain activity has been implicated in pathogenic processes in many tissues including the gut, brain, eyes, heart, lungs, pancreas, kidneys, vascular system, and skeletal muscle, suggesting that calpain inhibitors may serve as valuable therapeutic agents for a wide variety of diseases [4]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
