PTEN restoration and PIK3CB knockdown synergistically suppress glioblastoma growth in vitro and in xenografts |
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Authors: | Hongbo Chen Lin Mei Lanzhen Zhou Xiaomeng Shen Caiping Guo Yi Zheng Huijun Zhu Yongqiang Zhu Laiqiang Huang |
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Institution: | (1) School of Life Sciences, Tsinghua University, Beijing, 100084, China;(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; |
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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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