Endogenous p21WAF1/CIP1 status predicts the response of human tumor cells to wild-type p53 and p21WAF1/CIP1 overexpression

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Abstract
Expression of exogenous wild-type (wt) p53 protein can suppress the growth and/or induce apoptosis in different tumor cells. The effect of exogenous p21WAF1/CIP1 expression is more controversial: while it can induce apoptosis in some cells, it can protect against p53-mediated apoptosis in others. We used adenoviral vectors to introduce p53 and p21WAF1/CIP1 genes into human tumor cell lines with different p53 and/or p21WAF1/CIP1 status. The cell growth inhibition and the induction of apoptosis were measured. Overexpression of wt p53 induced more efficient growth inhibition and apoptosis in SW 620 (mutant p53) and HeLa (inactivated p53 protein) than in MCF-7 (wt p53) and CaCo-2 cell line, which was the most resistant to p53 overexpression despite the p53 mutation. Unlike HeLa and SW 620 cells, the basal p21 protein level was readily detected in CaCo-2 and MCF-7 cells. Overexpression of p21WAF1/CIP1 gene induced somewhat less pronounced growth inhibition of all cell lines tested, but it also induced apoptosis in HeLa and SW 620 cells. These results suggest that the basal, but not the inducible, levels of p21WAF1/CIP1 protein in tumor cells could protect from p53-mediated apoptosis. On the other hand, overexpression of p21WAF1/CIP1 gene itself can induce apoptosis in cells with no basal p21WAF1/CIP1 protein level. Possible mechanisms of the differential response to these genes are discussed.