title: PTEN restoration and PIK3CB knockdown synergistically suppress glioblastoma growth in vitro and in xenografts.
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.
authors.affiliation: School of Life Sciences, Tsinghua University, Beijing 100084, China.
authors.forename: Hongbo
authors.initials: H
authors.lastname: Chen
authors.forename: Lin
authors.initials: L
authors.lastname: Mei
authors.forename: Lanzhen
authors.initials: L
authors.lastname: Zhou
authors.forename: Xiaomeng
authors.initials: X
authors.lastname: Shen
authors.forename: Caiping
authors.initials: C
authors.lastname: Guo
authors.forename: Yi
authors.initials: Y
authors.lastname: Zheng
authors.forename: Huijun
authors.initials: H
authors.lastname: Zhu
authors.forename: Yongqiang
authors.initials: Y
authors.lastname: Zhu
authors.forename: Laiqiang
authors.initials: L
authors.lastname: Huang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D058534:Class I Phosphatidylinositol 3-Kinases; D004195:Disease Models, Animal; D005434:Flow Cytometry / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D005909:Glioblastoma / Q000473:pathology; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008954:Models, Biological; D051058:Oncogene Protein v-akt / Q000235:genetics / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism / Q000494:pharmacology; D013997:Time Factors; D014183:Transplantation, Heterologous / Q000379:methods
chemical_list: D034741:RNA, Small Interfering; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C497132:PIK3CB protein, human; D051058:Oncogene Protein v-akt; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human