P53 Plays a Key Role in the Apoptosis of Human Ovarian Cancer Cells Induced by Adenovirus-Mediated CRM197.

Abstract

Cross-reacting material 197 (CRM197) is a mutant form of the diphtheria toxin. Recent studies have found that CRM197 exerts an experimental antitumor effect on several types of tumors. This study applied a novel treatment of adenovirus-mediated CRM197 (AdCRM197) to human ovarian cancer cells. Interestingly, it was found that A2780 cells were sensitive to AdCRM197, but SKOV3 cells were resistant to it. Since SKOV3 cells are p53 deletion cells, while A2780 cells are p53 wild-type cells, it was postulated that p53 might play a key role in AdCRM197-induced apoptosis. This presumption was demonstrated by means of knockdown of p53 of the A2780 cells through lentivirus-mediated RNA interference. This knockdown resulted in the A2780 cells becoming resistant to AdCRM197. To verify this presumption further, the wild-type p53 gene in the SKOV3 cells was replaced with adenovirus-mediated p53 (Adp53). As expected, AdCRM197 plus Adp53 resulted in apoptosis of the SKOV3 cells. The combined treatment of AdCRM197 plus Adp53 also showed a good antitumor effect in the in vivo experiment on nude mice with xenograft tumors. Taking these results together, it is concluded that AdCRM197 induces apoptosis of human ovarian cancer cells via the p53 pathway. Moreover, it was found that Adp53 can reverse the resistance of p53-deletion human ovarian cancer cells to AdCRM197. The combination of AdCRM197 and Adp53 may be a potentially effective method for overcoming the resistance of p53-deficient human ovarian cancer to AdCRM197.