CEACAM6 attenuates adenovirus infection  by antagonizing viral trafficking in cancer cells.
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.
Centre for Molecular Oncology and Imaging, Institute of Cancer, Barts and The London School of Medicine and Dentistry, London, United Kingdom. yaohe.wang@cancer.org.uk
Yaohe
Y
Wang
Rathi
R
Gangeswaran
Xingbo
X
Zhao
Pengju
P
Wang
James
J
Tysome
Vipul
V
Bhakta
Ming
M
Yuan
C P
CP
Chikkanna-Gowda
Guozhong
G
Jiang
Dongling
D
Gao
Fengyu
F
Cao
Jennelle
J
Francis
Jinxia
J
Yu
Kangdong
K
Liu
Hongyan
H
Yang
Yunhan
Y
Zhang
Weidong
W
Zang
Claude
C
Chelala
Ziming
Z
Dong
Nick
N
Lemoine
D000256:Adenoviridae / Q000502:physiology* / Q000648:ultrastructure; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D003599:Cytoskeleton / Q000378:metabolism; D015536:Down-Regulation; D058851:GPI-Linked Proteins; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D046529:Microscopy, Electron, Transmission; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D034741:RNA, Small Interfering / Q000235:genetics; D013379:Substrate Specificity; D019061:src-Family Kinases / Q000378:metabolism
D015703:Antigens, CD; C504117:CEACAM6 protein, human; D015815:Cell Adhesion Molecules; D058851:GPI-Linked Proteins; D034741:RNA, Small Interfering; D019061:src-Family Kinases