title: PTEN loss represses glioblastoma tumor initiating cell differentiation via inactivation of Lgl1.
abstract: Glioblastoma multiforme is an aggressive and incurable type of brain tumor. A subset of undifferentiated glioblastoma cells, known as glioblastoma tumor initiating cells (GTICs), has an essential role in the malignancy of this disease and also appears to mediate resistance to radiation therapy and chemotherapy. GTICs retain the ability to differentiate into cells with reduced malignant potential, but the signaling pathways controlling differentiation are not fully understood at this time. PTEN loss is a very common in glioblastoma multiforme and leads to aberrant activation of the phosphoinositide 3-kinase pathway. Increased signalling through this pathway leads to activation of multiple protein kinases, including atypical protein kinase C. In Drosophila, active atypical protein kinase C has been shown to promote the self-renewal of neuroblasts, inhibiting their differentiation along a neuronal lineage. This effect is mediated by atypical protein kinase c-mediated phosphorylation and inactivation of Lgl, a protein that was first characterized as a tumour suppressor in Drosophila. The effects of the atypical protein kinase C/Lgl pathway on the differentiation status of GTICs, and its potential link to PTEN loss, have not been assessed previously. Here we show that PTEN loss leads to the phosphorylation and inactivation of Lgl by atypical protein kinase C in glioblastoma cells. Re-expression of PTEN in GTICs promoted their differentiation along a neuronal lineage. This effect was also seen when atypical protein kinase C was knocked down using RNA interference, and when a non-phosphorylatable, constitutively active form of Lgl was expressed in GTICs. Thus PTEN loss, acting via atypical protein kinase C activation and Lgl inactivation, helps to maintain GTICs in an undifferentiated state.
authors.affiliation: Centre for Cancer Therapeutics, Ottawa Hospital Research Institute, 501 Smyth Road, Ottawa, K1H 8L6, Canada.
authors.forename: Alexander
authors.initials: A
authors.lastname: Gont
authors.forename: Jennifer E L
authors.initials: JE
authors.lastname: Hanson
authors.forename: Sylvie J
authors.initials: SJ
authors.lastname: Lavictoire
authors.forename: Doris A
authors.initials: DA
authors.lastname: Parolin
authors.forename: Manijeh
authors.initials: M
authors.lastname: Daneshmand
authors.forename: Ian J
authors.initials: IJ
authors.lastname: Restall
authors.forename: Mathieu
authors.initials: M
authors.lastname: Soucie
authors.forename: Garth
authors.initials: G
authors.lastname: Nicholas
authors.forename: John
authors.initials: J
authors.lastname: Woulfe
authors.forename: Amin
authors.initials: A
authors.lastname: Kassam
authors.forename: Vasco F
authors.initials: VF
authors.lastname: Da Silva
authors.forename: Ian A J
authors.initials: IA
authors.lastname: Lorimer
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation / Q000502:physiology; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism*; D005909:Glioblastoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D064593:Heterografts; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D051059:PTEN Phosphohydrolase / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism; D034622:RNA Interference; D015398:Signal Transduction; D014162:Transfection
chemical_list: D003598:Cytoskeletal Proteins; C097906:LLGL1 protein, human; D011493:Protein Kinase C; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human
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