A Novel Role for Carcinoembryonic Antigen-Related Cell Adhesion Molecule 6 as a Determinant of Gemcitabine Chemoresistance in Pancreatic Adenocarcinoma Cells

Abstract

Most patients with pancreatic adenocarcinoma present with surgically incurable disease. Gemcitabine, the principal agent used to treat such patients, has little impact on outcome. Overexpression of carcinoembryonic antigen-related cell adhesion molecule (CEACAM) 6, a feature of this malignancy, is associated with resistance to anoikis and increased metastasis. The purpose of this study was to determine the role of CEACAM6 in cellular chemoresistance to gemcitabine. CEACAM6 was stably overexpressed in Capan2 cells, which inherently express very low levels of the protein. Suppression of CEACAM6 expression was achieved in BxPC3 cells, which inherently overexpress CEACAM6, by stable transfection of a CEACAM6 small interfering RNA-generating vector. The effects of modulating CEACAM6 expression on gemcitabine-induced cytotoxicity were determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide cytotoxicity assay, flow cytometric apoptosis quantification, caspase profiling, and Western analysis of cytoplasmic cytochrome c release. The roles of Akt and c-Src kinases as downstream targets of CEACAM6 signaling were examined. Stable overexpression of CEACAM6 in Capan2 increased gemcitabine chemoresistance, whereas CEACAM6 gene silencing in BxPC3 markedly increased the sensitivity of these cells to gemcitabine. Differential expression of CEACAM6 modulates Akt activity in a c-Src-dependent manner, and CEACAM6 overexpression appears to protect cells from cytochrome c-induced caspase 3 activation and apoptosis.

CEACAM6 gene expression in intrahepatic cholangiocarcinoma

“…One possible explanation of the relationship between overexpression of CEACAM6 and gemcitabine resistance is that CEACAM6 overexpression may protect cells from cytochrome c-induced caspase 3 activation and apoptosis via Akt or c-Src activation. This cytoprotective pathway may contribute to gemcitabine chemoresistance (Duxbury et al, 2004e). …”

Anoikis: an emerging hallmark in health and diseases

“…Really, activation of Src has been reported in various cancers characterized by anoikis resistance [48,69,114,115]. Actually, a crucial role is played by the modulation of PI3K-Akt signal pathway, regulated by PTEN-mediated dephosphorylation [116].…”

CEACAM6 attenuates adenovirus infection by antagonizing viral trafficking in cancer cells

“…To this end, we screened a panel of pancreatic cancer cell lines for sensitivity to adenovirus and then examined differential gene expression between adenovirus-sensitive and -insensitive cells by Affymetrix array analysis. Interestingly, we found that expression of carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6), a gene with a well-documented role in tumor invasion, metastasis, and drug resistance (17)(18)(19)(20), correlates with the sensitivity of tumor cells to adenovirus. Further stepwise investigations demonstrated that CEACAM6 blocked adenovirus trafficking to the nucleus through the Src pathway, which interferes with the cytoskeleton of cancer cells, resulting in attenuated infectability by adenovirus.…”