Abstract
Conditionally replicating adenoviruses (CRAds), or oncolytic adenoviruses, such as E1B55K-deleted adenovirus, are attractive anticancer agents. However, the therapeutic efficacy of E1B55K-deleted adenovirus for refractory solid tumors has been limited. Environmental stress conditions may induce nuclear accumulation of YB-1, which occurs in multidrug-resistant and adenovirus-infected cancer cells. Overexpression and nuclear localization of YB-1 are associated with poor prognosis and tumor recurrence in various cancers. Nuclear YB-1 transactivates the multidrug resistance 1 (MDR1) genes through the Y-box. Here, we developed a novel E1B55K-deleted adenovirus driven by the MDR1 promoter, designed Ad5GS3. We tested the feasibility of using YB-1 to transcriptionally regulate Ad5GS3 replication in cancer cells and thereby to enhance antitumor efficacy. We evaluated synergistic antitumor effects of oncolytic virotherapy in combination with chemotherapy. Our results show that adenovirus E1A induced E2F-1 activity to augment YB-1 expression, which shut down host protein synthesis in cancer cells during adenovirus replication. In cancer cells infected with Ad5WS1, an E1B55K-deleted adenovirus driven by the E1 promoter, E1A enhanced YB-1 expression, and then further phosphorylated Akt, which, in turn, triggered nuclear translocation of YB-1. Ad5GS3 in combination with chemotherapeutic agents facilitated nuclear localization of YB-1 and, in turn, upregulated the MDR1 promoter activity and enhanced Ad5GS3 replication in cancer cells. Thus, E1A, YB-1, and the MDR1 promoter form a positive feedback loop to promote Ad5GS3 replication in cancer cells, and this regulation can be further augmented when chemotherapeutic agents are added. In the in vivo study, Ad5GS3 in combination with etoposide synergistically suppressed tumor growth and prolonged survival in NOD/SCID mice bearing human lung tumor xenografts. More importantly, Ad5GS3 exerted potent oncolytic activity against clinical advanced lung adenocarcinoma, which was associated with elevated levels of nuclear YB-1 and cytoplasmic MDR1 expression in the advanced tumors. Therefore, Ad5GS3 may have therapeutic potential for cancer treatment, especially in combination with chemotherapy. Because YB-1 is expressed in a broad spectrum of cancers, this oncolytic adenovirus may be broadly applicable.
Highlights
Replicating adenoviruses (CRAds) or oncolytic adenoviruses have been exploited as a cancer treatment option because they selectively replicate in and kill cancer cells [1, 2]
Adenovirus E1A and Ad5WS1 upregulates YB-1 expression through E2F-1, which is associated with replication of Ad5WS1 in cancer cells
RT-PCR, quantitative real-time RTPCR, and immunoblot analyses confirmed overexpression of E1A mRNA and protein in MCF-7 cells transfected with an E1A expression plasmid, which resulted in upregulation of mRNA and protein expression of YB-1 (Figure 1B, 1C)
Summary
Replicating adenoviruses (CRAds) or oncolytic adenoviruses have been exploited as a cancer treatment option because they selectively replicate in and kill cancer cells [1, 2]. The mechanism of tumor-selective replication of E1B55K-deleted adenoviruses, including a possible role of p53, is still unclear. Both adenovirus infection and oncogenic transformation induce similar signaling cascades in eukaryotic cells. It was reported that the ability of tumor cells to provide the host protein shutoff and late viral RNA export functions determines their permissiveness for the replication of E1B55K-deleted adenovirus [5, 6]. To develop novel CRAds with high antitumor efficacy and tumor selectivity, apart from understanding the functions of viral genes, further explorations of host factors and signaling pathways that may determine tumor-selective replication of E1B55Kdeleted adenovirus are needed
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
