癌胚抗原通过干扰TRAIL-R2（DR5）信号传导抑制结肠癌细胞的失巢凋亡。

Carcinoembryonic antigen inhibits anoikis in colorectal carcinoma cells by interfering with TRAIL-R2 (DR5) signaling.

作者信息

Samara Raed N, Laguinge Luciana M, Jessup J Milburn

机构信息

Department of Oncology, Georgetown University Medical Center, Washington, District of Columbia 20057, USA.

出版信息

Cancer Res. 2007 May 15;67(10):4774-82. doi: 10.1158/0008-5472.CAN-06-4315.

DOI:10.1158/0008-5472.CAN-06-4315

PMID:17510406

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.

摘要

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。