The MDM4 Inhibitor CEP-1347 Activates Wild-type p53 in Ovarian Clear Cell Carcinoma Cells and Potently Inhibits their Growth
Ovarian clear cell carcinoma (OCCC) is a subtype of ovarian cancer, in which The effects of CEP-1347 as well as the knockdown of MDM4 or p53 on the mRNA and/or protein expression of components of the p53 pathway, including MDM4, in human OCCC cell lines with and without p53 mutation were examined by RT-PCR and western blot analyses. Dye exclusion and colony formation assays were used to examine the effects of CEP-1347 on cell growth. CEP-1347 decreased MDM4 and increased p53 protein expression, and also induced the expression of p21, a CDK inhibitor, in a p53-dependent manner in OCCC cells with wild-type p53. In these cells, the knockdown-mediated inhibition of MDM4 expression increased the expression of p53 and p21. Furthermore, CEP-1347 potently inhibited the growth and clonogenic survival of OCCC cells without exhibiting toxicity in normal cells at clinically relevant concentrations. The present results suggest the potential of targeting MDM4 with CEP-1347 as a therapeutic approach for the treatment of OCCC with wild-type p53.