Exogenous wt-p53 protein is active in transformed cells but not in their non-transformed counterparts: Implications for cancer gene therapy without tumor targeting

Background: Expression of exogenous wild-type p53 (wt-p53) protein in tumor cells can suppress the transformed phenotype whereas it does not apparently induce detrimental effects in non-transformed cells. This observation may provide a molecular basis for p53-mediated gene therapy of p53-sensitive cancers without the need for tumor targeting. Methods: To understand the molecular mechanisms responsible for this different behavior in tumor versus normal cells, biochemical and functional analyses of exogenous wt-p53 protein were performed on non-transformed C₂C₁₂ myoblasts and their transformed counterparts, the C₂-ras cells. Results: The exogenous wt-p53 protein, which induced persistent growth arrest only in transformed C₂-ras cells, was shown to be significantly more stable in transformed than in non-transformed cells. This different stability was due to different p53 proteolytic degradation. Moreover, constitutively, exogenous wt-p53 protein was found to be transcriptionally active only in C₂-ras cells but it could also be activated in C₂C₁₂ cells by genotoxic damage. Conclusions: Non-transformed C₂C¹² cells present regulatory system(s) which control the expression and the activity of exogenously expressed wt-p53 protein probably through degradation and maintenance in a latent form. This regulatory system is lost/inactivated upon transformation.