Adenovirus-mediated truncated Bid overexpression induced by the Cre/LoxP system promotes the cell apoptosis of CD133+ ovarian cancer stem cells

• Published in: Oncology reports Vol. 37; no. 1; pp. 155 - 162
• Main Authors: Long, Qifang, Yang, Ru, Lu, Weixian, Zhu, Weipei, Zhou, Jundong, Zheng, Cui, Zhou, Dongmei, Yu, Ling, Wu, Jinchang
• Format: Journal Article
• Language: English
• Published: Greece D.A. Spandidos 01.01.2017; Spandidos Publications UK Ltd
• Subjects: AC133 Antigen - metabolism; Adenoviridae - genetics; Animals; Apoptosis; Apoptosis - genetics; BH3 Interacting Domain Death Agonist Protein - chemistry; BH3 Interacting Domain Death Agonist Protein - genetics; cancer stem cells; Cancer therapies; CD133; cell apoptosis; Codon, Nonsense; Cytochrome; Female; Gene expression; Gene Expression Regulation, Neoplastic; Gene Transfer Techniques; Genetic Therapy - methods; Genetic Vectors; Growth factors; HEK293 Cells; Humans; Infections; Integrases - genetics; Laboratory animals; Liver cancer; Metastasis; Mice; Mice, SCID; Mitochondria; Mutagenesis, Site-Directed; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; Neoplastic Stem Cells - physiology; Ovarian cancer; Ovarian Neoplasms - genetics; Ovarian Neoplasms - metabolism; Ovarian Neoplasms - pathology; Ovarian Neoplasms - therapy; Plasmids; Stem cells; tBid; Tumor Cells, Cultured; Xenograft Model Antitumor Assays; United States > US
• ISSN: 1021-335X; 1791-2431
• DOI: 10.3892/or.2016.5263

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.