Changes in E2F binding after phenylbutyrate-induced differentiation of Caco-2 colon cancer cells

Differentiation agents use existing cellular systems to induce neoplastic c ells to regain a normal phenotype and/or to cause growth arrest and therefo re may offer novel chemotherapeutic approaches to treating solid tumors. In this study, we demonstrate in Caco-2 colon cancer cells that the different iation agent phenylbutyrate (PB) causes a decrease in viable cells, an incr ease in cell differentiation, and a G(1)-S-phase block, The mechanism of th is last effect is related to a PB-induced increase in p27(Kip1), leading to a decrease in the activity of cyclin-dependent kinase 2 (CDK2), a positive regulator of the G(1)-S-phase cell cycle transition. Consistent with the d ecreased CDK2 kinase activity, we also observed a decrease in the phosphory lation state of the retinoblastoma protein after PB treatment. This was ass ociated with increased binding and consequent inactivation of E2F, a transa ctivator of genes that regulate the G(1) to S phase cell cycle transition. These data suggest that the differentiation agent PB inhibits tumor growth by limiting the availability of active E2F, with a subsequent G(1)-S-phase block, Additional studies should show whether PB is a clinically effective therapeutic agent against colorectal cancer.