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PTEN restoration and PIK3CB knockdown synergistically suppress glioblastoma growth in vitro and in xenografts

  • Laboratory Investigation - Human/Animal Tissue
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Abstract

Glioblastoma is the most frequent and malignant glioma in adults. To develop an effective gene therapy strategy for glioblastoma, we investigated the anti-proliferative effects of phosphatase and tensin homolog (PTEN) restoration and siRNAs specifically targeting PIK3CB and PIK3CA on PTEN-deficient glioblastoma cells in vitro and in subcutaneous xenografts. Restoration of PTEN or knockdown of PIK3CB, but not PIK3CA, in glioblastoma cells markedly down-regulates the phosphorylation level of AKT, inhibits cell proliferation and colony formation, arrests the cell cycle at the G0/G1 stage, and promotes caspase-dependent apoptosis. Combined treatment with PTEN restoration and PIK3CB knockdown shows strong synergy. PTEN restoration or PIK3CB knockdown is also able to efficiently inhibit the growth of human U251 glioblastoma xenografts in nude mice, while tumor growth is entirely suppressed by a combination of the two treatments. In addition, we found that the mRNA levels of inhibitors of apoptosis proteins (IAPs) are reduced in U251 cells by PTEN restoration, suggesting that combined antitumor effects may also be partly attributed to the inhibition of the IAP pathway by PTEN restoration. Collectively, our results demonstrate that PI3 K isoforms play specific roles in tumorigenesis, and that combined treatment of PTEN restoration and PIK3CB siRNA is a promising gene therapy strategy for PTEN-deficient gliomas.

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Acknowledgments

We are grateful for the fundings (to L.H.) from the Shenzhen Municipal Government and Bureau of Science Technology and Information through the programs of Shenzhen National Key Lab of Health Science and Technology and the Key Lab of Gene and Antibody Therapy; from the Ministry of Science and Technology of China through the National “973” Key Research Program grant 2005CCA03500; and from the National Natural Science Foundation of China (NSFC) through grant 30570960.

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Authors and Affiliations

  1. School of Life Sciences, Tsinghua University, Beijing, 100084, China

    Hongbo Chen, Lin Mei, Xiaomeng Shen, Caiping Guo, Yi Zheng, Huijun Zhu, Yongqiang Zhu & Laiqiang Huang

  2. The Shenzhen Key Lab of Gene and Antibody Therapy, Center for Biotech and BioMedicine and Division of Life Sciences, Graduate School at Shenzhen, Tsinghua University, The University Town, Shenzhen, 518055, Guangdong, China

    Hongbo Chen, Lin Mei, Lanzhen Zhou, Xiaomeng Shen, Caiping Guo, Yi Zheng, Huijun Zhu, Yongqiang Zhu & Laiqiang Huang

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  1. Hongbo Chen
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  2. Lin Mei
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Correspondence to Laiqiang Huang.

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Chen, H., Mei, L., Zhou, L. et al. PTEN restoration and PIK3CB knockdown synergistically suppress glioblastoma growth in vitro and in xenografts. J Neurooncol 104, 155–167 (2011). https://doi.org/10.1007/s11060-010-0492-2

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  • DOI: https://doi.org/10.1007/s11060-010-0492-2

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