Carcinoembryonic antigen inhibits anoikis in colorectal carcinoma cells by interfering with TRAIL-R2 (DR5) signaling.
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.
Samara
Raed N
RN
Department of Oncology, Georgetown University Medical Center, Washington, District of Columbia 20057, USA.
Laguinge
Luciana M
LM
Jessup
J Milburn
JM
D023102:Anoikis / Q000502:physiology*; D002272:Carcinoembryonic Antigen / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D053181:Caspase 8 / Q000378:metabolism; D061945:Caspase Inhibitors; D002448:Cell Adhesion / Q000502:physiology; D015179:Colorectal Neoplasms / Q000378:metabolism / Q000473:pathology*; D019073:HT29 Cells; D006801:Humans; D016023:Integrins / Q000378:metabolism; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism / Q000556:secondary; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology
D002272:Carcinoembryonic Antigen; D061945:Caspase Inhibitors; D016023:Integrins; D010446:Peptide Fragments; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; C505639:TNFRSF10B protein, human; D053181:Caspase 8