The human carcinoembryonic antigen (CEA) GPI anchor mediates anoikis inhibition by inactivation of the intrinsic death pathway.
Human carcinoembryonic antigen (CEA) is a cell surface adhesion molecule member of the Immunoglobulin Superfamily (IgSF). Aberrant upregulation of CEA is a common feature found in a wide variety of human cancers such as colon, breast and lung. Previous in vitro and in vivo results have demonstrated that CEA can have tumorigenic effects including the inhibition of cell differentiation and anoikis, a specific type of apoptosis triggered by the absence of extracellular matrix-cell contacts. In the present work, we investigate the involvement of the caspase cascade in CEA-mediated inhibition of anoikis and the structural requirements for this signal. Expression of CEA and/or a chimeric protein consisting of the NCAM extracellular domain attached to the CEA-GPI anchor correlates with an early inactivation of caspase-9 and activation of the PI3-K/Akt survival pathway, and at later times, inactivation of caspase-8. The CEA-mediated caspase inactivation as well as activation of Akt was not observed by expression of a CEA molecule incapable of self-binding (DeltaNCEA). These results suggest that the intrinsic caspase pathway is involved in the inhibitory effects of anoikis by CEA and this signal is dependent on the presence of self-adhesive extracellular domains and a CEA-GPI anchor.
Camacho-Leal
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Department of Biochemistry and McGill Cancer Center, McGill University, Promenade Sir-William Osler, Montreal, Quebec, Canada.
Stanners
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D000818:Animals; D023102:Anoikis / Q000502:physiology*; D017209:Apoptosis / Q000502:physiology*; D015153:Blotting, Western; D002272:Carcinoembryonic Antigen / Q000235:genetics / Q000378:metabolism*; D053453:Caspase 9 / Q000378:metabolism; D061945:Caspase Inhibitors; D002478:Cells, Cultured; D045304:Cytochromes c / Q000378:metabolism; D004789:Enzyme Activation; D017261:Glycosylphosphatidylinositols / Q000235:genetics / Q000378:metabolism*; D020287:In Situ Nick-End Labeling; D020935:MAP Kinase Signaling System / Q000502:physiology; D032446:Myoblasts / Q000166:cytology / Q000378:metabolism*; D019006:Neural Cell Adhesion Molecules / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015398:Signal Transduction
D002272:Carcinoembryonic Antigen; D061945:Caspase Inhibitors; D017261:Glycosylphosphatidylinositols; D019006:Neural Cell Adhesion Molecules; D011993:Recombinant Fusion Proteins; D045304:Cytochromes c; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D053453:Caspase 9