Development of Differentiation-directed Cancer Gene Therapy with p21

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A cycline-dependent kinase inhibitor p21 is induced in thc process of differentiation. To develop a novel gene-based anti-cancer therapy that can induce a welI-differentiated state in cancer cells, we examined antitumor offeet of the p21 gene transfer on human cancer cells. A recombinant adenovirus-mediated transient overexpression of p21 on TE-1 human esophageal cancer cells exhibited morphological changes indicative of differentiation, such as enlarged nuclei and flattened shape. Moreover, expression of involucrin protein, a differentiation marker of squamous cells, was up-regulated after the p21 gene transfer. We also found that retinoic acid receptor (RAR) was positively regulated by the p21 gene transfer in DLD-1 (colon), 1-11299 (lung), H460 (lung), and TE-13 (esophagus) human cancer cell lines. Increased expression of RAR induced the sensitivity to retinoic acid (RA) in RA-resistant DLD-1 cancer cells, resulting in the synergistic antitumor effect of the p21 gene transfer and RA treatment. These observations suggest that adenovirus-mediated p21 gene transfer can induce differentiation in human cancer cells and that the p21 gene has important implications for a differentiation-directed molecular therapy.