title: PKCι depletion initiates mitotic slippage-induced senescence in glioblastoma.
abstract: Cellular senescence is a tumor suppressor mechanism where cells enter a permanent growth arrest following cellular stress. Oncogene-induced senescence (OIS) is induced in non-malignant cells following the expression of an oncogene or inactivation of a tumor suppressor. Previously, we have shown that protein kinase C iota (PKCι) depletion induces cellular senescence in glioblastoma cells in the absence of a detectable DNA damage response. Here we demonstrate that senescent glioblastoma cells exhibit an aberrant centrosome morphology. This was observed in basal levels of senescence, in p21-induced senescence, and in PKCι depletion-induced senescence. In addition, senescent glioblastoma cells are polyploid, Ki-67 negative and arrest at the G1/S checkpoint, as determined by expression of cell cycle regulatory proteins. These markers are all consistent with cells that have undergone mitotic slippage. Failure of the spindle assembly checkpoint to function properly can lead to mitotic slippage, resulting in the premature exit of mitotic cells into the G1 phase of the cell cycle. Although in G1, these cells have the replicated DNA and centrosomal phenotype of a cell that has entered mitosis and failed to divide. Overall, we demonstrate that PKCι depletion initiates mitotic slippage-induced senescence in glioblastoma cells. To our knowledge, this is the first evidence of markers of mitotic slippage directly in senescent cells by co-staining for senescence-associated β-galactosidase and immunofluorescence markers in the same cell population. We suggest that markers of mitotic slippage be assessed in future studies of senescence to determine the extent of mitotic slippage in the induction of cellular senescence.
authors.affiliation: a Centre for Cancer Therapeutics; Ottawa Hospital Research Institute ; Ottawa , ON Canada.|b Department of Biochemistry ; Microbiology and Immunology; University of Ottawa ; Ottawa , ON Canada.
authors.forename: Ian J
authors.initials: IJ
authors.lastname: Restall
authors.affiliation: a Centre for Cancer Therapeutics; Ottawa Hospital Research Institute ; Ottawa , ON Canada.
authors.forename: Doris A E
authors.initials: DA
authors.lastname: Parolin
authors.affiliation: a Centre for Cancer Therapeutics; Ottawa Hospital Research Institute ; Ottawa , ON Canada.
authors.forename: Manijeh
authors.initials: M
authors.lastname: Daneshmand
authors.affiliation: a Centre for Cancer Therapeutics; Ottawa Hospital Research Institute ; Ottawa , ON Canada.
authors.forename: Jennifer E L
authors.initials: JE
authors.lastname: Hanson
authors.affiliation: a Centre for Cancer Therapeutics; Ottawa Hospital Research Institute ; Ottawa , ON Canada.|b Department of Biochemistry ; Microbiology and Immunology; University of Ottawa ; Ottawa , ON Canada.
authors.forename: Manon A
authors.initials: MA
authors.lastname: Simard
authors.affiliation: a Centre for Cancer Therapeutics; Ottawa Hospital Research Institute ; Ottawa , ON Canada.|b Department of Biochemistry ; Microbiology and Immunology; University of Ottawa ; Ottawa , ON Canada.
authors.forename: Megan E
authors.initials: ME
authors.lastname: Fitzpatrick
authors.affiliation: a Centre for Cancer Therapeutics; Ottawa Hospital Research Institute ; Ottawa , ON Canada.|b Department of Biochemistry ; Microbiology and Immunology; University of Ottawa ; Ottawa , ON Canada.
authors.forename: Ritesh
authors.initials: R
authors.lastname: Kumar
authors.affiliation: a Centre for Cancer Therapeutics; Ottawa Hospital Research Institute ; Ottawa , ON Canada.
authors.forename: Sylvie J
authors.initials: SJ
authors.lastname: Lavictoire
authors.affiliation: a Centre for Cancer Therapeutics; Ottawa Hospital Research Institute ; Ottawa , ON Canada.|b Department of Biochemistry ; Microbiology and Immunology; University of Ottawa ; Ottawa , ON Canada.|c Department of Medicine ; University of Ottawa ; Ottawa , ON Canada.
authors.forename: Ian A J
authors.initials: IA
authors.lastname: Lorimer
mesh_terms: D015415:Biomarkers / Q000378:metabolism; D059447:Cell Cycle Checkpoints; D016922:Cellular Senescence; D018385:Centrosome / Q000648:ultrastructure; D004249:DNA Damage; D005909:Glioblastoma / Q000473:pathology*; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D008938:Mitosis / Q000502:physiology*; D011123:Polyploidy; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D013312:Stress, Physiological; D000099293:Protein Kinase C-lambda
chemical_list: D015415:Biomarkers; D007527:Isoenzymes; D011493:Protein Kinase C; D000099293:Protein Kinase C-lambda
keywords: PKCι; Protein kinase C iota; glioblastoma; mitotic slippage; senescence