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The CEACAM1-mediated apoptosis pathway is activated by CEA and triggers dual cleavage of CEACAM1
1Institute for Clinical Chemistry, University Hospital Mannheim of the Ruprecht-Karls University Heidelberg, Mannheim, Germany.
Abstract:
Marked reduction in apoptosis is a hallmark of early colon tumour growth and the vast majority of these tumours exhibit a loss of expression of the glycoprotein carcinoembryonic-antigen-related cell adhesion molecule 1 (CEACAM1). We recently reported that the CEACAM1 functions as a mediator of apoptosis implicating this cell surface protein in early tumour development. However, the mechanistic involvement of CEACAM1 in cell death pathways is unclear. Here, we show that apoptosis triggers cleavage of the long form of CEACAM1 (CEACAM1-4L) at intracellular and extracellular sites in Jurkat cells and HEK293 cells. Signalling through CEACAM1 leads to caspase activation including caspase-1 and -3 and also involves non-caspase proteases. Moreover, we provide evidence that the naturally occurring CEACAM family member CEA is an inducer of CEACAM1-mediated apoptosis in HT29 colon cancer cells, an effect that depends on the abundance of CEACAM1 on the cell surface. Together, our results demonstrate that the CEACAM1-dependent cell death pathway involves dual cleavage of CEACAM1 and caspase activation and can be activated by CEA.
Insights
Carcinoembryonic-antigen-related cell adhesion molecule 1 (CEACAM1) loss is key in colon tumors. This study reveals CEACAM1 cleavage and caspase activation mediate apoptosis, a pathway CEA can trigger.
Area of Science:
- Cell Biology
- Molecular Oncology
- Cancer Research
Background:
- Reduced apoptosis is characteristic of early colon tumor development.
- Loss of carcinoembryonic-antigen-related cell adhesion molecule 1 (CEACAM1) expression is common in these tumors.
- CEACAM1 acts as a mediator of apoptosis, suggesting its role in early tumor progression.
Purpose of the Study:
- To elucidate the mechanistic involvement of CEACAM1 in cell death pathways.
- To investigate the cleavage sites and signaling mechanisms of CEACAM1 during apoptosis.
- To determine if the CEACAM family member CEA can induce CEACAM1-mediated apoptosis.
Main Methods:
- Apoptosis induction in Jurkat and HEK293 cells.
- Analysis of CEACAM1 cleavage at intracellular and extracellular sites.
- Assessment of caspase activation (caspase-1, -3) and non-caspase protease involvement.
- Investigation of CEA's effect on CEACAM1-mediated apoptosis in HT29 colon cancer cells.
Main Results:
- Apoptosis triggers dual cleavage of the long form of CEACAM1 (CEACAM1-4L).
- CEACAM1 signaling activates caspases (-1, -3) and non-caspase proteases.
- Carcinoembryonic antigen (CEA) induces CEACAM1-mediated apoptosis in colon cancer cells.
- The CEACAM1 abundance on the cell surface influences CEA-induced apoptosis.
Conclusions:
- The CEACAM1-dependent cell death pathway involves dual CEACAM1 cleavage and caspase activation.
- CEA can activate this CEACAM1-dependent apoptotic pathway in colon cancer cells.
- Understanding this pathway offers potential therapeutic targets for colon cancer treatment.
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