Abstract
Carcinoembryonic antigen (CEA) is a tumor marker that is associated with metastasis, poor response to chemotherapy of colorectal cancer (CRC), and anoikis, a form of apoptosis caused by cell detachment from matrix that is dependent on TRAIL-R2 (DR5) and caspase-8 activation in CRC. Although CEA is a homophilic binding protein that may provide survival signals through homotypical cell aggregation, we now report that CEA binds TRAIL-R2 (DR5) directly in two-hybrid assays to decrease anoikis through the extrinsic pathway. Deletion of the PELPK sequence (delPELPK) of CEA (delPELPK CEA) restores sensitivity to anoikis while it maintains its cell aggregation function. Wild-type (WT) CEA also increases experimental hepatic metastasis, whereas the delPELPK CEA does not. Thus, membrane CEA interacts with DR5 to inhibit anoikis and increase metastatic potential in CRC.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Anoikis / physiology*
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Carcinoembryonic Antigen / biosynthesis
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Carcinoembryonic Antigen / genetics
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Carcinoembryonic Antigen / metabolism*
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Caspase 8 / metabolism
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Caspase Inhibitors
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Cell Adhesion / physiology
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Colorectal Neoplasms / metabolism
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Colorectal Neoplasms / pathology*
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HT29 Cells
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Humans
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Integrins / metabolism
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Liver Neoplasms / genetics
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Liver Neoplasms / metabolism
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Liver Neoplasms / secondary
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Peptide Fragments / genetics
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Peptide Fragments / metabolism
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Protein Binding
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Receptors, TNF-Related Apoptosis-Inducing Ligand / antagonists & inhibitors
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Receptors, TNF-Related Apoptosis-Inducing Ligand / metabolism*
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Signal Transduction / physiology
Substances
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Carcinoembryonic Antigen
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Caspase Inhibitors
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Integrins
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Peptide Fragments
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Receptors, TNF-Related Apoptosis-Inducing Ligand
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TNFRSF10B protein, human
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Caspase 8