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Mdm2 antagonist Nutlin‐3 induces apoptosis in p53 mutant human colon carcinoma cells

Mdm2 antagonist Nutlin‐3 disrupts p53‐Mdm2 interaction and activates p53 signaling. Most human cancers have p53 mutations and are resistant to apoptosis induced by chemotherapeutic drugs. This study investigated the role of Nutlin‐3 in apoptosis of human colon carcinoma cells (Caco‐2) with a mutant p53. Caco‐2 cells were insensitive to TNF‐α/CHX and camptothecin (CPT)‐mediated apoptosis. However, Nutlin‐3 induced DNA fragmentation and apoptosis in Caco‐2 cells by itself. Induction of apoptosis by Nutlin‐3 correlated with increased levels of E2F1 protein, which led to increased expression of its target p73, a homologue of p53. High basal levels of the anti‐apoptotic Bcl‐xL protein normally present in Caco‐2 cells, decreased in response to Nutlin‐3. E2F1 and p73 activation by Nutlin‐3 increased SIVA protein levels, which sequestered Bcl‐xL, caused mitochondrial permeability changes and activated caspases‐9, and ‐3. Pre‐treatment of cells with cycloheximide (CHX) prevented Nutlin‐3‐induced increase of SIVA and protected cells from apoptosis. Our results indicate that Nutlin‐3 can induce apoptosis in the absence of functional p53 by modulating levels of E2F1 and p73 and may have therapeutic implications in various forms of human cancer. Supported by NIDDK grant DK‐16505.