Decreased PKC-α Expression Increases Cellular Proliferation, Decreases Differentiation, and Enhances the Transformed Phenotype of CaCo-2 Cells

Previous studies have shown that PKC-α protein expression is decreased in sporadic human colon cancers, as well as in colonic tumors of rats induced by chemical carcinogens. To elucidate the potential role of PKC-α on several phenotypic characteristics of colon cancer cells, we have transfected cDNAs for PKC-α in sense or antisense orientations into CaCo-2 cells, a human colonic adenocarcinoma cell line. Transfected clones were isolated that demonstrated ∼3-fold increases (sense transfectants) and ∼95% decreases (antisense transfectants) in PKC-α expression with no significant alterations in other PKC isoforms. Transfection of CaCo-2 cells with PKC-α in the antisense orientation resulted in enhanced proliferation and decreased differentiation, as well as in a more aggressive transformed phenotype compared with empty vector-transfected control cells. In contrast, cells transfected with PKC-α cDNA in the sense orientation demonstrated decreased proliferation, enhanced differentiation, and an attenuated tumor phenotype compared with these control cells. These data show that alterations in the expression of PKC-α induce changes in the proliferation, differentiation, and tumorigenicity of CaCo-2 cells. Furthermore, these findings indicate that loss of PKC-α expression in sporadic human and chemically induced colonic cancers may confer a relative growth advantage during colonic malignant transformation.