Ubiquitous induction of p53 in tumor cells by antisense inhibition of MDM2expression

Background: The MDM2 oncogene functions as a negative feedback regulator of the p53 tumor suppressor. Abnormal expression of MDM2 in tumors may attenu ate the p53-mediated growth arrest and apoptosis response, resulting in inc reased cell proliferation and resistance to chemotherapy. Materials and Methods: We have developed phosphorothioate antisense oligode oxynucleotides optimized for inhibition of MDM2 expression and investigated the role of MDM2 in a large panel of tumor cell lines. Results: Inhibition of MDM2 expression in 15 tumor types containing wild-ty pe p53 results in a significant induction of nuclear p53 accumulation. The increase in p53 level is due to prolonged half-life and is associated with an increase in p53 transcriptional activity, growth inhibition, or apoptosi s. Inhibition of MDM2 expression is also sufficient to induce nuclear p53 a ccumulation in several cell lines with cytoplasmic p53. Conclusions: The MDM2 negative feedback loop is important for maintenance o f p53 at a low level by promoting p53 degradation. Nuclear export and degra dation by MDM2 may contribute to the p53 nuclear exclusion phenotype. Inhib ition of MDM2 expression can effectively activate p53 in most tumor types, including those without MDM2 overexpression, and may have broad anti-tumor potential.