Abstract 5405: Apoptosis induction in cancer cells by the simultaneous transduction of p53 and artificial miRNAs based on the screening of genome-wide shRNA library

Abstract

Abstract Gene transfer involving p53 is viewed as a potentially effective cancer therapy, but does not result in a good therapeutic response in all human cancers. Several p53 target genes have an inhibitory effect on p53-mediated apoptosis. Therefore, if the induction of these genes by p53 is selectively suppressed, the therapeutic effectiveness would be improved. In previous study, we constructed a replication-deficient recombinant adenovirus that encoded co-cistronic p53 and artificial microRNAs (miRNAs) targeting p21, a representative p53 target gene which have an anti-apoptotic effect, resulting in p53 expression and the suppression of p21 induction simultaneously. In colorectal and hepatocellular carcinoma cells, the infection with the adenovirus vector augmented apoptosis and suppressed tumor growth as compared to an adenovirus that expressed p53 alone in vitro and in vivo. In this study, we simultaneously infected the vectors which express artificial miRNAs targeting other anti-apoptotic genes and evaluated the therapeutic effectiveness of p53 expression in combination with the suppression of several anti-apoptotic p53 target genes. Co-infection with these vectors suppressed the induction of anti-apoptotic target genes and induced apoptosis more efficiently in cancer cells. To identify other RNAi targets which prevent p53-induced apoptosis, we have screened the genome-wide lentiviral shRNA library in the cancer cells which resist p53-induced apoptosis. After the infection with p53 or control adenovirus, the cell populations expressing each shRNA were quantified by microarray. As a result, we found that several cell populations expressing specific shRNAs were significantly decreased in p53-infected cells compared with control cells. This result indicated that the suppression of specific targets by RNAi restored the apoptotic response by p53 transduction in cancer cells which originally resist p53-induced apoptosis. These results suggest that the transduction of p53 and specific miRNAs may be effective as a cancer therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5405. doi:10.1158/1538-7445.AM2011-5405