title: Serine/threonine protein phosphatase 6 modulates the radiation sensitivity of glioblastoma.
abstract: Increasing the sensitivity of glioblastoma cells to radiation is a promising approach to improve survival in patients with glioblastoma multiforme (GBM). This study aims to determine if serine/threonine phosphatase (protein phosphatase 6 (PP6)) is a molecular target for GBM radiosensitization treatment. The GBM orthotopic xenograft mice model was used in this study. Our data demonstrated that the protein level of PP6 catalytic subunit (PP6c) was upregulated in the GBM tissue from about 50% patients compared with the surrounding tissue or control tissue. Both the in vitro survival fraction of GBM cells and the patient survival time were highly correlated or inversely correlated with PP6c expression (R(2)=0.755 and -0.707, respectively). We also found that siRNA knockdown of PP6c reduced DNA-dependent protein kinase (DNA-PK) activity in three different GBM cell lines, increasing their sensitivity to radiation. In the orthotopic mice model, the overexpression of PP6c in GBM U87 cells attenuated the effect of radiation treatment, and reduced the survival time of mice compared with the control mice, while the PP6c knocking-down improved the effect of radiation treatment, and increased the survival time of mice. These findings demonstrate that PP6 regulates the sensitivity of GBM cells to radiation, and suggest small molecules disrupting or inhibiting PP6 association with DNA-PK is a potential radiosensitizer for GBM.
authors.affiliation: Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Institute of Medical Science, Shanghai JiaoTong University School of Medicine, Shanghai, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Shen
authors.forename: Y
authors.initials: Y
authors.lastname: Wang
authors.forename: K
authors.initials: K
authors.lastname: Sheng
authors.forename: X
authors.initials: X
authors.lastname: Fei
authors.forename: Q
authors.initials: Q
authors.lastname: Guo
authors.forename: J
authors.initials: J
authors.lastname: Larner
authors.forename: X
authors.initials: X
authors.lastname: Kong
authors.forename: Y
authors.initials: Y
authors.lastname: Qiu
authors.forename: J
authors.initials: J
authors.lastname: Mi
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D020134:Catalytic Domain; D045744:Cell Line, Tumor; D051747:DNA-Activated Protein Kinase / Q000378:metabolism; D005909:Glioblastoma / Q000532:radiotherapy*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D011839:Radiation, Ionizing; D014183:Transplantation, Heterologous
chemical_list: D034741:RNA, Small Interfering; D051747:DNA-Activated Protein Kinase; D010749:Phosphoprotein Phosphatases; C106079:protein phosphatase 6