Samara Raed N, Laguinge Luciana M, Jessup J Milburn
Department of Oncology, Georgetown University Medical Center, Washington, District of Columbia 20057, USA.
Cancer Res. 2007 May 15;67(10):4774-82. doi: 10.1158/0008-5472.CAN-06-4315.
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.
癌胚抗原（CEA）是一种肿瘤标志物，与转移、结直肠癌（CRC）化疗反应不佳以及失巢凋亡有关，失巢凋亡是一种由细胞与基质脱离引起的凋亡形式，在CRC中依赖于肿瘤坏死因子相关凋亡诱导配体受体2（TRAIL-R2，又称死亡受体5，DR5）和半胱天冬酶-8的激活。尽管CEA是一种同源结合蛋白，可能通过同型细胞聚集提供生存信号，但我们现在报告，在双杂交试验中CEA直接结合TRAIL-R2（DR5），通过外源性途径减少失巢凋亡。CEA的PELPK序列缺失（delPELPK CEA）恢复了对失巢凋亡的敏感性，同时保持其细胞聚集功能。野生型（WT）CEA也会增加实验性肝转移，而delPELPK CEA则不会。因此，膜CEA与DR5相互作用以抑制失巢凋亡并增加CRC的转移潜能。
