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 3

CEACAM6 functionally affects adenovirus infection.

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CEACAM6 functionally affects adenovirus infection. (A) Expression of CEA...
(A) Expression of CEACAM6 protein in pancreatic cancer cell lines and engineered subclone cell lines as analyzed by Western blotting. (B) CEACAM6 expression in vector-transfected PaTu8988t (top) and CEACAM6-transfected PaTu8988t cell lines (bottom) by confocal microscopy, showing CEACAM6 expression on membrane and in cytoplasm. Blue (DAPI staining) indicates nuclei; green, CEACAM6; original magnification, ×600. (C) Sensitivity of CEACAM6-overexpressing cell lines and their counterparts to adenovirus as assayed by MTS. The EC50 values were increased 4-fold in CEACAM6-transfected PaTu8988t and HCT116 cells compared with their counterparts. (D) The infectivity of adenovirus Ad-GFP in stable clones of PaTu8988t-Hyg and PaTu8988t-CEACAM6 by FACS analysis at 48 hours after infection with Ad-CMV-GFP adenovirus. (E) Adenovirus replication in stable clones of PaTu8988t-Hyg and PaTu8988t-CEACAM6 (infected at an MOI of 100 pt/cell). (F) The expression of CEACAM6 as analyzed by qPCR in Suit-2 cell line after treatment with control siRNA and the CEACAM6-specific SMARTpool at various time points. (G) The expression of CEACAM6 protein by Western blotting after treatment with control siRNA, and the CEACAM6-specific SMARTpool at various time points. (H) Cell death of control siRNA– and CEACAM6-specific SMARTpool siRNA–pretreated Suit-2 cells after adenovirus infection at MOI of 50 and 100 pt/cell. (I) The infectivity of adenovirus Ad-GFP in control and CEACAM6-specific SMARTpool siRNA–pretreated Suit-2 cells by FACS at 48 hours after infection with Ad-CMV-GFP adenovirus. (J) Adenovirus replication in control and CEACAM6-specific SMARTpool siRNA–pretreated Suit-2 cells (infected at an MOI of 100 pt/cell) by 50% tissue culture infective dose (TCID50) assay. All experiments were repeated at least 3 times. **P < 0.01, ***P < 0.001.