DEREGULATION OF HEXOSE TRANSPORTER EXPRESSION IN CACO-2 CELLS BY RAS AND POLYOMA-MIDDLE-T ONCOGENES

We investigated whether the oncogenic activation of p21(ras) or pp60(c -src), which is frequently observed in colorectal cancers, induced alt erations of sugar uptake in human colonic cells. We therefore examined hexose transporter expression and/or activity in Caco-2 cells transfe cted either with an activated human (Val-12) Ha-ras gene or with the p olyoma middle T (PyMT) oncogene, a constitutive activator of pp60(c-sr c) tyrosine kinase activity. Experiments were performed at day 20 of c ulture, when Caco-2 cells express enterocyte-specific GLUT-2, GLUT-5, and SGLT-1 transporters in addition to GLUT-1 and GLUT-3. Along with i ncreased glucose consumption rates, both oncogene-transfected cells ex hibited increased levels of GLUT-1 and GLUT-3 mRNAs and/or immunoreact ive proteins compared with control vector Caco-2 cells. In contrast, o ncogene-transfected cells lost GLUT-2, GLUT-5, and SGLT-1 expression a s determined by Northern and/or Western blot analyses and/or specific transport assays. The oncogene-induced repressive effect on these ente rocyte-specific hexose transporters extended to brush-border hydrolase s and villin but not to tight junctional protein ZO-1. In conclusion, oncogenic p21(ras) and PyMT/pp60(c-src) induce severe deregulation of hexose transporter expression in Caco-2 cells, which is manifested by 1) increased GLUT-1 and GLUT-3 expression and 2) repression of GLUT-2, GLUT-5, and SGLT-1, which parallels repression of some markers of the enterocyte-like differentiated phenotype of Caco-2 cells.