Abstract 2862: Bioengineered oncolytic adenovirus induces autophagic cell death through an E2F1-microRNA-7-epidermal growth factor receptor axis

Abstract

Abstract Autophagy is known to have a cytoprotective role under various cellular stresses, such as deprivation of nutrients, hypoxia and interruption of growth signaling. In contrast, autophagy also results in robust cell death as an important safeguard mechanism that protects the organism against invading pathogens and unwanted cancer cells. Recent accumulating evidences have suggested the implication of autophagy on the oncolytic adenovirus-mediated cell death in human cancer cells. However, the molecular mechanism underlying oncolytic adenovirus-mediated autophagic cell death remains unclear. We previously generated a genetically engineered oncolytic adenovirus (Telomelysin®: OBP-301) that replicates and induces autophagic cell death against human cancer cells in a telomerase-dependent manner. As microRNA (miRNA), a post-transcriptional regulator of gene expression, has been recently shown to regulate diverse cell fates including autophagy, we hypothesized that OBP-301 infection induces autophagic cell death through miRNA modulation in human cancer cells. In this study, we attempted the role of miRNA on the OBP-301-mediated autophagic cell death in human cancer cells. We used 3 human cancer cell lines (H1299, A549 and T.Tn), that showed different sensitivities to OBP-301. OBP-301 infection upregulated miR-7 expression in OBP-301-sensitive human cancer cell lines (H1299 and A549), but not OBP-301-resistant human cancer cell line (T.Tn). Expression levels of miR-7 upregulated after OBP-301 infection was significantly associated with OBP-301-mediated cytopathic activity and autophagic cell death, which was confirmed by western blot for autophagy-related proteins (LC3-I/II, Atg5 and p62). We also revealed that OBP-301-mediated miR-7 upregulation mainly depended on enhanced expression of the E2F1 protein after OBP-301 infection. Furthermore, ectopic expression of miR-7 in human cancer cell lines suppressed cell viability and subsequently induced autophagy through inhibition of epidermal growth factor receptor (EGFR) expression. OBP-301 infection efficiently suppressed EGFR expression, which was significantly associated with miR-7 upregulation and cytopathic activity, in human cancer cell lines. Our results suggest that oncolytic adenovirus OBP-301 induces autophagic cell death through an E2F1-miR-7-EGFR pathway in human cancer cells, providing a novel insight into the molecular mechanism of an anticancer virotherapy. 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 2862. doi:10.1158/1538-7445.AM2011-2862