title: Etoposide enhances antitumor efficacy of MDR1-driven oncolytic adenovirus through autoupregulation of the MDR1 promoter activity.
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.
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Bing-Hua
authors.initials: BH
authors.lastname: Su
authors.affiliation: Department of Urology, Tainan Hospital, Ministry of Health and Welfare, Executive Yuan, Tainan, Taiwan.
authors.forename: Gia-Shing
authors.initials: GS
authors.lastname: Shieh
authors.affiliation: Division of Thoracic Surgery, Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Yau-Lin
authors.initials: YL
authors.lastname: Tseng
authors.affiliation: Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Ai-Li
authors.initials: AL
authors.lastname: Shiau
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Chao-Liang
authors.initials: CL
authors.lastname: Wu
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics; D021581:Active Transport, Cell Nucleus; D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy* / Q000821:virology; D000077192:Adenocarcinoma of Lung; D000256:Adenoviridae / Q000235:genetics* / Q000254:growth & development; D017500:Adenovirus E1A Proteins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017024:Chemotherapy, Adjuvant; D050687:E2F1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D005047:Etoposide / Q000494:pharmacology*; D005240:Feasibility Studies; D015972:Gene Expression Regulation, Neoplastic; D015967:Gene Expression Regulation, Viral; D057809:HEK293 Cells; D006706:Homeostasis; D054884:Host-Pathogen Interactions; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy* / Q000821:virology; D061986:MCF-7 Cells; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D050130:Oncolytic Virotherapy / Q000379:methods*; D050504:Oncolytic Viruses / Q000235:genetics* / Q000254:growth & development; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D013997:Time Factors; D014158:Transcription, Genetic; D014162:Transfection; D014779:Virus Replication; D023041:Xenograft Model Antitumor Assays; D051840:Y-Box-Binding Protein 1 / Q000235:genetics / Q000378:metabolism
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D017500:Adenovirus E1A Proteins; D000972:Antineoplastic Agents, Phytogenic; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; D051840:Y-Box-Binding Protein 1; C070856:YBX1 protein, human; D005047:Etoposide; D051057:Proto-Oncogene Proteins c-akt
keywords: E1A; MDR1; YB-1; oncolytic adenovirus