title: Inhibition of glioblastoma malignancy by Lgl1.
abstract: lethal giant larvae (lgl) was first identified as a tumor suppressor in Drosophila, where its loss repressed the differentiation and promoted the invasion of neuroblasts, the Drosophila equivalent of the neural stem cell. Recently we have shown that a human homolog of Lgl, Lgl1 (LLGL1), is constitutively phosphorylated and inactivated in glioblastoma cells; this occurs as a downstream consequence of PTEN loss, one of the most frequent genetic events in glioblastoma. Here we have investigated the consequences of this loss of functional Lgl1 in glioblastoma in vivo. We used a doxycycline-inducible system to express a non-phosphorylatable, constitutively active version of Lgl1 (Lgl3SA) in either a glioblastoma cell line or primary glioblastoma cells isolated under neural stem cell culture conditions from patients. In both types of cells, expression of Lgl3SA, but not wild type Lgl1, inhibited cell motility in vitro. Induction of Lgl3SA in intracerebral xenografts markedly reduced the in vivo invasion of primary glioblastoma cells. Lgl3SA expression also induced the differentiation of glioblastoma cells in vitro and in vivo along the neuronal lineage. Thus the central features of Lgl function as a tumor suppressor in Drosophila are conserved in human glioblastoma.
authors.affiliation: Centre for Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, K1H 8L6, Canada. Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: Alexander
authors.initials: A
authors.lastname: Gont
authors.affiliation: Centre for Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, K1H 8L6, Canada.
authors.forename: Jennifer E L
authors.initials: JE
authors.lastname: Hanson
authors.affiliation: Centre for Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, K1H 8L6, Canada.
authors.forename: Sylvie J
authors.initials: SJ
authors.lastname: Lavictoire
authors.affiliation: Centre for Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, K1H 8L6, Canada. Department of Pathology and Laboratory Medicine, University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: Manijeh
authors.initials: M
authors.lastname: Daneshmand
authors.affiliation: Centre for Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, K1H 8L6, Canada. Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: Garth
authors.initials: G
authors.lastname: Nicholas
authors.affiliation: Centre for Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, K1H 8L6, Canada. Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, Canada. Department of Pathology and Laboratory Medicine, University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: John
authors.initials: J
authors.lastname: Woulfe
authors.affiliation: Department of Surgery, University of Ottawa, Ottawa, Ontario, Canada. Aurora St. Luke's Medical Center, Aurora Health Care, Milwaukee, WI 53215, USA.
authors.forename: Amin
authors.initials: A
authors.lastname: Kassam
authors.affiliation: Department of Surgery, University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: Vasco F
authors.initials: VF
authors.lastname: Da Silva
authors.affiliation: Centre for Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, K1H 8L6, Canada. Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, Canada. Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: Ian A J
authors.initials: IA
authors.lastname: Lorimer
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D004318:Doxycycline / Q000737:chemistry; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D016513:Mice, SCID; D018715:Microscopy, Video; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D010766:Phosphorylation
chemical_list: D003598:Cytoskeletal Proteins; C097906:LLGL1 protein, human; D004318:Doxycycline