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[Involvement of ICE/CED 3 family proteases in antitumor agent-induced apoptosis]
Abstract:
Some chemotherapeutic agents, as well as TNF and Fas, induce apoptotic cell death in tumor cells, but the cellular components involved in the process have not yet been identified. Interleukin 1 beta converting enzyme (ICE) is a mammalian homolog of CED-3, a protein required for programmed cell death in nematode Caenorhabditis elegans. We found that a selective inhibitor of ICE/ced 3 family proteases, benzyloxycarbonyl Asp CH2OC(O) 2 6,-dichlorobenzene (Z-Asp-CH2-DCB). completely blocked the apoptotic cell death of human leukemia cells caused by etoposide, camptothecin, 1-beta-D-arabinofuranosyl cytosine (Ara-C) and adriamycin. Moreover, in antitumor agent-treated U937 cells, an ICE-like (CPP32-like) protease was strongly activated. These results indicate that ICE/ ced 3 family proteases are involved in antitumor agent-induced apoptosis. Activation of ICE family proteases plays a key role in apoptosis. However, the subsequent mechanisms resulting in apoptosis are largely unknown. We identified actin as a substrate of ICE family proteases. Cleavage of actin and other substrate proteins by ICE family proteases could be critical in the ongoing process of antitumor agent-induced apoptosis in tumor cells.
Insights
Interleukin 1 beta converting enzyme (ICE) proteases are crucial for chemotherapy-induced apoptosis in tumor cells. These proteases, including ICE-like CPP32, cleave substrates like actin, driving programmed cell death.
Area of Science:
- Molecular Biology
- Cell Biology
- Biochemistry
Context:
- Chemotherapeutic agents and signals like TNF and Fas induce tumor cell apoptosis.
- The specific cellular components mediating this process remained largely unidentified.
- Interleukin 1 beta converting enzyme (ICE), a homolog of C. elegans CED-3, is implicated in programmed cell death.
Purpose:
- To investigate the role of ICE/ced-3 family proteases in chemotherapy-induced apoptosis of tumor cells.
- To identify cellular substrates targeted by ICE family proteases during apoptosis.
Summary:
- A selective ICE/ced-3 family protease inhibitor (Z-Asp-CH2-DCB) blocked etoposide, camptothecin, Ara-C, and adriamycin-induced apoptosis in human leukemia cells.
- ICE-like (CPP32-like) protease activity was significantly elevated in U937 cells treated with antitumor agents.
- Actin was identified as a substrate cleaved by ICE family proteases, suggesting its cleavage is critical for apoptosis.
Impact:
- ICE/ced-3 family proteases are key mediators of antitumor agent-induced apoptosis.
- The cleavage of actin and other proteins by ICE family proteases is a critical step in the apoptotic pathway.
- This research elucidates molecular mechanisms underlying chemotherapy-induced tumor cell death.