Inhibition of glioblastoma malignancy by Lgl1
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Alexander Gont1,2, Jennifer E.L. Hanson1, Sylvie J. Lavictoire1, Manijeh Daneshmand1,3, Garth Nicholas1,5, John Woulfe1,2,3, Amin Kassam4,6, Vasco F. Da Silva4, Ian A.J. Lorimer1,2,5
1Centre for Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, K1H 8L6, Canada
2Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, Canada
3Department of Pathology and Laboratory Medicine, University of Ottawa, Ottawa, Ontario, Canada
4Department of Surgery, University of Ottawa, Ottawa, Ontario, Canada
5Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada
6Aurora St. Luke’s Medical Center, Aurora Health Care, Milwaukee, WI 53215, USA
Ian A. J. Lorimer, e-mail: [email protected]
Keywords: Glioblastoma, glioma, Lgl, Lgl1, PTEN, invasion
Received: July 04, 2014 Accepted: October 08, 2014 Published: October 15, 2014
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.
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