Mdm2 Is Required for Survival and Growth of p53-Deficient Cancer Cells.

Abstract

<i>p53</i> deletion prevents the embryonic lethality of normal tissues lacking Mdm2, suggesting that cells can survive without Mdm2 if p53 is also absent. Here we report evidence challenging this view, with implications for therapeutically targeting Mdm2. Deletion of <i>Mdm2</i> in T-cell lymphomas or sarcomas lacking p53 induced apoptosis and G₂ cell-cycle arrest, prolonging survival of mice with these tumors. <i>p53</i>^-/- fibroblasts showed similar results, indicating that the effects of Mdm2 loss extend to premalignant cells. <i>Mdm2</i> deletion in <i>p53</i>^-/- cells upregulated p53 transcriptional target genes that induce apoptosis and cell-cycle arrest. <i>Mdm2</i> deletion also increased levels of p73, a p53 family member. RNAi-mediated attenuation of p73 rescued the transcriptional and biological effects of Mdm2 loss, indicating that p73 mediates the consequences of <i>Mdm2</i> deletion. In addition, <i>Mdm2</i> deletion differed from blocking Mdm2 interaction with p53 family members, as Nutlin-3 induced G₁ arrest but did not activate apoptosis in <i>p53</i>^-/- sarcoma cells. Our results indicate that, in contrast to current dogma, Mdm2 expression is required for cell survival even in the absence of p53. Moreover, our results suggest that p73 compensates for loss of p53 and that targeting Mdm2 in p53-deficient cancers has therapeutic potential. <i>Cancer Res; 77(14); 3823-33. ©2017 AACR</i>.