Overexpression of the p21(sdi1) gene induces senescence-like state in human cancer cells: implication for senescence-directed molecular therapy for cancer

Normal cells in a culture enter a nondividing state after a finite number o f population doubling, which is termed replicative senescence, whereas canc er cells have unlimited proliferative potential and are thought to exhibit an immortal phenotype by escaping from senescence. The p21 gene (also known as sdi1), which encodes the cyclin-dependent kinase inhibitor, is expresse d at high levels in senescent cells and contributes to the growth arrest. T o examine if the p21(sdi1) gene transfer could induce senescence in human c ancer cells, we utilized an adenoviral vector-based expression system and f our human cancer cell lines differing in their p53 status. Transient overex pression of p21(sdi1) on cancer cells induced quiescence by arresting the c ell cycle at the G(1) phase and exhibited morphological changes, such as en larged nuclei as well as a flattened cellular shape, specific to the senesc ence phenotype. We also showed that p21(sid1)-transduced cancer cells expre ssed beta-galactosidase activity at pH 6.0, which is known to be a marker o f senescence. Moreover, the polymerase chain reaction-based assay demonstra ted that levels of telomerase activity were significantly lower in p21(sdi1 )-expressing cells compared to parental cancer cells. These observations pr ovide the evidence that p21(sdi1) overexpression could induce a senescence- like state and reduce telomerase activity in human cancer cells, suggesting that these novel p21(sdi1) functions may have important implications for a nticancer therapy.