Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 119, Issue 6, Pages 1604-1615Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI37905
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Funding
- Cancer Research UK [C633-A6253/A6251]
- Nature Sciences Foundation of China [30530800]
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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.
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