CEACAM6 attenuates adenovirus infection by antagonizing viral trafficking in cancer cells

J Clin Invest. 2009 Jun;119(6):1604-15. doi: 10.1172/JCI37905.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoviridae / physiology*
  • Adenoviridae / ultrastructure
  • Antigens, CD / genetics
  • Antigens, CD / metabolism*
  • Cell Adhesion Molecules / genetics
  • Cell Adhesion Molecules / metabolism*
  • Cell Line
  • Colorectal Neoplasms / genetics
  • Colorectal Neoplasms / metabolism*
  • Colorectal Neoplasms / pathology*
  • Cytoskeleton / metabolism
  • Down-Regulation
  • GPI-Linked Proteins
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Microscopy, Electron, Transmission
  • Pancreatic Neoplasms / genetics
  • Pancreatic Neoplasms / metabolism*
  • Pancreatic Neoplasms / pathology*
  • RNA, Small Interfering / genetics
  • Substrate Specificity
  • src-Family Kinases / metabolism

Substances

  • Antigens, CD
  • CEACAM6 protein, human
  • Cell Adhesion Molecules
  • GPI-Linked Proteins
  • RNA, Small Interfering
  • src-Family Kinases