CEACAM6 attenuates adenovirus infection by antagonizing viral trafficking in cancer cells
Yaohe Wang, … , Ziming Dong, Nick Lemoine
Yaohe Wang, … , Ziming Dong, Nick Lemoine
Published May 1, 2009
Citation Information: J Clin Invest. 2009;119(6):1604-1615. https://doi.org/10.1172/JCI37905.
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CEACAM6 attenuates adenovirus infection by antagonizing viral trafficking in cancer cells

Abstract

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 well as for the development of more potent adenovirus-based therapeutics.

Authors

Yaohe Wang, Rathi Gangeswaran, Xingbo Zhao, Pengju Wang, James Tysome, Vipul Bhakta, Ming Yuan, C.P. Chikkanna-Gowda, Guozhong Jiang, Dongling Gao, Fengyu Cao, Jennelle Francis, Jinxia Yu, Kangdong Liu, Hongyan Yang, Yunhan Zhang, Weidong Zang, Claude Chelala, Ziming Dong, Nick Lemoine

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Figure 4

Effect of CEACAM6 on the life cycle of adenovirus.

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Effect of CEACAM6 on the life cycle of adenovirus. (A) Quantitation of E...
(A) Quantitation of E1A copy number after Ad5 binding in PaTu8988t-Hyg and PaTu8988t-CEACAM6 cells at 4°C for 1 hour (P = 0.5679) by qPCR. (B) qPCR quantitation of E1A copy number after Ad5 binding in control and CEACAM6-specific SMARTpool siRNA–pretreated Suit-2 cells at 4°C for 1 hour (P = 0.3619). (C) qPCR quantitation of E1A copy number of uninternalized adenovirus in PaTu8988t-Hyg and PaTu8988t-CEACAM6 cells (P > 0.05) at different time points. (D) qPCR quantitation of E1A copy number of uninternalized adenovirus in control and CEACAM6-specific SMARTpool siRNA–treated Suit-2 cells (P > 0.05) at different time points. (E) Adenovirus attachment and trafficking observed by TEM in CEACAM6-modulated cells and their counterparts after Ad5 was allowed to bind at 4°C for 1 hour and allowed to internalize and traffic to the nuclei at 37°C for various time points. N, nucleus. Original magnification, ×60,000. (F) Confocal images of stable cells with labeled Ad5 particle (red) and α-tubulin (green) after Ad5 was bound at 4°C for 1 hour and allowed to internalize and traffic to nuclei at 37°C for various times; original magnification, ×600. (G) Quantitation of E1A copy number in the nucleus after Ad5 was bound at 4°C for 1 hour and allowed to traffic at 37°C for 30 and 60 minutes in PaTu8988t-Hyg and PaTu8988t-CEACAM6 cells by qPCR. (H) qPCR quantitation of E1A copy number in the nuclei after Ad5 was allowed to bind at 4°C for 1 hour and allowed to traffic at 37°C for 30 and 60 minutes in control and CEACAM6-specific siRNA–treated Suit-2 cells by qPCR. ***P < 0.001.