DECREASED PKC-ALPHA EXPRESSION INCREASES CELLULAR PROLIFERATION, DECREASES DIFFERENTIATION, AND ENHANCES THE TRANSFORMED PHENOTYPE OF CACO-2 CELLS

Previous studies have shown that PKC-alpha protein expression is decre ased in sporadic human colon cancers, as well as in colonic tumors of rats induced by chemical carcinogens, To elucidate the potential role of PKC-alpha on several phenotypic characteristics of colon cancer cel ls, we have transfected cDNAs for PKC-alpha in sense or antisense orie ntations into CaCo-2 cells, a human colonic adenocarcinoma cell line. Transfected clones were isolated that demonstrated similar to 3-fold i ncreases (sense transfectants) and similar to 95% decreases (antisense transfectants) in PKC-alpha expression with no significant alteration s in other PKC isoforms, Transfection of CaCo-2 cells with PKC-alpha i n the antisense orientation resulted in enhanced proliferation and dec reased differentiation, as well as in a more aggressive transformed ph enotype compared with empty vector-transfected control cells. In contr ast, cells transfected with PKC-alpha cDNA in the sense orientation de monstrated decreased proliferation, enhanced differentiation, and an a ttenuated tumor phenotype compared with these control cells. These dat a show that alterations in the expression of PKC-alpha induce changes in the proliferation, differentiation, and tumorigenicity of CaCo-2 ce lls. Furthermore, these findings indicate that loss of PkC-alpha expre ssion in sporadic human and chemically induced colonic cancels may con fer a relative growth advantage during colonic malignant transformatio n.