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.