Oncolytic replication-competent adenovirus suppresses tumor angiogenesis through preserved E1A region

Abstract

An adenovirus (Adv) retaining normal E1A but lacking the 55 kDa E1B protein replicates preferentially in TP53-deficient cancer cells including pancreatic cancer cell lines, resulting in the oncolysis of the tumor. When tumor cells are exposed to hypoxia, hypoxia-inducible factor-1a (HIF-1a) is stabilized and activated to promote the transcription of several genes such as vascular endothelial growth factor (VEGF), but in the presence of E1A hypoxia-induced VEGF m-RNA synthesis is inhibited by E1A binding to p300. In this study, we demonstrated that the cancer cells infected with a mutant Adv in which the p300 binding site in E1A was partially deleted induced a higher expression level of VEGF as compared to those of Adv with normal E1A. An immunoprecipitation study for E1A confirmed that mutant E1A had a reduced binding capacity for p300. Although the expressions of HIF-1a m-RNA were almost the same in both cancer cells infected with the mutant Adv and those with the wild Adv, the amount of HIF-1a protein in cancer cells infected with the wild E1A Adv was lower than in those infected with the mutant E1A type Adv. In vivo, in contrast to the angiogenesis treated with mutant E1A, wild-E1A inhibited tumor angiogenesis significantly. These results suggested that E1A suppressed the production of VEGF and inhibited tumor angiogenesis by binding with p300, resulting in the inhibition of the HIF1a-mediated transcription of genes through binding to HRE. This study demonstrates, for the first time, the effect of an oncolytic replication-competent Adv in inhibiting tumor angiogenesis.

MT1-MMP silencing by an shRNA-armed glioma-targeted conditionally replicative adenovirus (CRAd) improves its anti-glioma efficacy in vitro and in vivo

“…Additionally, retargeting of the CRAd to CD46 receptor via replacement of the wild type Ad5 fiber with that of the Ad3 allows incorporation of an additional payload in the E3 region of the adenoviral genome, while retaining a strong anti-cancer effect. Several scientific reports have demonstrated that adenoviral OVs suppress tumor angiogenesis by expressing products of the E1A genomic regions [43,44]. Additional suppression of IL8 or VEGF improves the anti-cancer effect mediated by CRAds [17,41].…”

WSB1 promotes tumor metastasis by inducing pVHL degradation

“…Furthermore, the increase of HIF-1α level by WSB1 through pVHL's degradation may explain why high levels of HIF-1α are detected in normoxic regions of human tumors with functional pVHL (Supplemental Fig. S4B; Zhong et al 1999;Akakura et al 2001;Saito et al 2006).…”

“…S4B). Previously, several studies have also shown high HIF-1α protein levels in cancer cells under normoxic conditions (Zhong et al 1999;Akakura et al 2001;Jung et al 2006;Saito et al 2006). Therefore, WSB1 might be responsible for increased HIF-1α levels under normoxic conditions.…”

ONYX-411, a conditionally replicative oncolytic adenovirus, induces cell death in anaplastic thyroid carcinoma cell lines and suppresses the growth of xenograft tumors in nude mice

“…Saito et al 25 have recently demonstrated that the E1A region of adenovirus suppressed the production of vascular endothelial growth factor and inhibited tumor angiogenesis by binding with p300, further emphasizing the potential utility of adenovirus-mediated gene therapy. The decreased neovasculogenesis might also be an indirect effect of tumor size.…”