CEACAM6 attenuates adenovirus infection by antagonizing viral trafficking in cancer cells
CEACAM6 attenuates adenovirus infection by antagonizing viral trafficking in cancer cells
复制标题
CEACAM6 通过拮抗癌细胞中的病毒运输来减轻腺病毒感染
DOI：
10.1172/jci37905
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发表时间：
2009-06-01
影响因子：
15.9
通讯作者：
Lemoine, Nick
中科院分区：
文献类型：
--
作者：
Wang, Yaohe;Gangeswaran, Rathi;Lemoine, Nick
肿瘤发生过程中癌细胞表面分子和细胞内信号通路的变化使得基于腺病毒的癌症治疗效率低下。在这里，我们发现癌胚抗原相关细胞粘附分子6（CEACAM6）是一种限制腺病毒载体感染癌细胞能力的细胞蛋白。我们已经证明，CEACAM6 可以拮抗 Src 信号通路，下调癌细胞细胞骨架蛋白，并阻止腺病毒贩运到人胰腺癌细胞的细胞核。与 CEACAM6 过表达类似，Src 选择性抑制剂治疗显着减少了这些癌细胞和正常人上皮细胞中的腺病毒复制。在小鼠异种移植肿瘤模型中，siRNA介导的CEACAM6敲低也显着增强了溶瘤腺病毒的抗肿瘤作用。我们认为，CEACAM6 相关信号通路可能成为开发生物标志物的潜在目标，以预测患者对基于腺病毒的疗法的反应，就像开发更有效的基于腺病毒的疗法一样。
The changes in cancer cell surface molecules and intracellular signaling pathways during tumorigenesis make delivery of adenovirus-based cancer therapies inefficient. Here we have identified carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6) as a cellular protein that restricts the ability of adenoviral vectors to infect cancer cells. We have demonstrated that CEACAM6 can antagonize the Src signaling pathway, downregulate cancer cell cytoskeleton proteins, and block adenovirus trafficking to the nucleus of human pancreatic cancer cells. Similar to CEACAM6 overexpression, treatment with a Src-selective inhibitor significantly reduced adenovirus replication in these cancer cells and normal human epithelial cells. In a mouse xenograft tumor model, siRNA-mediated knockdown of CEACAM6 also significantly enhanced the antitumor effect of an oncolytic adenovirus. We propose that CEACAM6-associated signaling pathways could be potential targets for the development of biomarkers to predict the response of patients to adenovirus-based therapies, as wen as for the development of more potent adenovirus-based therapeutics.