title: Adenovirus-mediated truncated Bid overexpression induced by the Cre/LoxP system promotes the cell apoptosis of CD133+ ovarian cancer stem cells.
abstract: Cancer stem cells are a small subset of cancer cells that contribute to cancer progression, metastasis, chemoresistance and recurrence. CD133-positive (CD133+) ovarian cancer cells have been identified as ovarian cancer stem cells. Adenovirus-mediated gene therapy is an innovative therapeutic method for cancer treatment. In the present study, we aimed to develop a new gene therapy to specifically eliminate CD133+ ovarian cancer stem cells by targeting CD133. We used the Cre/LoxP system to augment the selective expression of the truncated Bid (tBid) gene as suicide gene therapy in CD133+ ovarian cancer stem cells. The adenovirus (Ad)-CD133-Cre expressing Cre recombinase under the control of the CD133 promoter and Ad-CMV-LoxP-Neo-LoxP-tBid expressing tBid under the control of the CMV promoter were successfully constructed using the Cre/LoxP switching system. The co-infection of Ad-CMV-LoxP-Neo-LoxP-tBid and Ad-CD133-Cre selectively induced tBid overexpression, which inhibited cell growth and triggered the cell apoptosis of CD133+ ovarian cancer stem cells. The Cre/LoxP system-mediated tBid overexpression activated the pro-apoptotic signaling pathway and augmented the cytotoxic effect of cisplatin in CD133+ ovarian cancer stem cells. Furthermore, in xenograft experiments, co-infection with the two recombinant adenoviruses markedly suppressed tumor growth in vivo and promoted cell apoptosis in tumor tissues. Taken together, the present study provides evidence that the adenovirus-mediated tBid overexpression induced by the Cre/LoxP system can effectively eliminate CD133+ ovarian cancer stem cells, representing a novel therapeutic strategy for the treatment of ovarian cancer.
authors.affiliation: Department of Radio-Oncology, Nanjing Medical University Affiliated Suzhou Hospital, Suzhou, Jiangsu 215001, P.R. China.
authors.forename: Qifang
authors.initials: Q
authors.lastname: Long
authors.affiliation: Department of Gynecology and Obstetrics, Nanjing Medical University Affiliated Suzhou Hospital, Suzhou, Jiangsu 215001, P.R. China.
authors.forename: Ru
authors.initials: R
authors.lastname: Yang
authors.affiliation: Department of Gynecology and Obstetrics, Nanjing Medical University Affiliated Suzhou Hospital, Suzhou, Jiangsu 215001, P.R. China.
authors.forename: Weixian
authors.initials: W
authors.lastname: Lu
authors.affiliation: Department of Gynecology and Obstetrics, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215004, P.R. China.
authors.forename: Weipei
authors.initials: W
authors.lastname: Zhu
authors.affiliation: Department of Radio-Oncology, Nanjing Medical University Affiliated Suzhou Hospital, Suzhou, Jiangsu 215001, P.R. China.
authors.forename: Jundong
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Department of Gynecology and Obstetrics, Nanjing Medical University Affiliated Suzhou Hospital, Suzhou, Jiangsu 215001, P.R. China.
authors.forename: Cui
authors.initials: C
authors.lastname: Zheng
authors.affiliation: Department of Gynecology and Obstetrics, Nanjing Medical University Affiliated Suzhou Hospital, Suzhou, Jiangsu 215001, P.R. China.
authors.forename: Dongmei
authors.initials: D
authors.lastname: Zhou
authors.affiliation: Department of Gynecology and Obstetrics, Nanjing Medical University Affiliated Suzhou Hospital, Suzhou, Jiangsu 215001, P.R. China.
authors.forename: Ling
authors.initials: L
authors.lastname: Yu
authors.affiliation: Department of Radio-Oncology, Nanjing Medical University Affiliated Suzhou Hospital, Suzhou, Jiangsu 215001, P.R. China.
authors.forename: Jinchang
authors.initials: J
authors.lastname: Wu
mesh_terms: D000071916:AC133 Antigen / Q000378:metabolism; D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D051023:BH3 Interacting Domain Death Agonist Protein / Q000737:chemistry / Q000235:genetics*; D018389:Codon, Nonsense; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D057809:HEK293 Cells; D006801:Humans; D019426:Integrases / Q000235:genetics*; D051379:Mice; D016513:Mice, SCID; D016297:Mutagenesis, Site-Directed; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology / Q000502:physiology*; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000071916:AC133 Antigen; D051023:BH3 Interacting Domain Death Agonist Protein; C494814:BID protein, human; D018389:Codon, Nonsense; C000606023:PROM1 protein, human; C045073:Cre recombinase; D019426:Integrases