title: Polo-like kinase 1 inhibition kills glioblastoma multiforme brain tumor cells in part through loss of SOX2 and delays tumor progression in mice.
abstract: Glioblastoma multiforme (GBM) ranks among the deadliest types of cancer and given these new therapies are urgently needed. To identify molecular targets, we queried a microarray profiling 467 human GBMs and discovered that polo-like kinase 1 (PLK1) was highly expressed in these tumors and that it clustered with the proliferative subtype. Patients with PLK1-high tumors were more likely to die from their disease suggesting that current therapies are inactive against such tumors. This prompted us to examine its expression in brain tumor initiating cells (BTICs) given their association with treatment failure. BTICs isolated from patients expressed 110-470 times more PLK1 than normal human astrocytes. Moreover, BTICs rely on PLK1 for survival because the PLK1 inhibitor BI2536 inhibited their growth in tumorsphere cultures. PLK1 inhibition suppressed growth, caused G(2) /M arrest, induced apoptosis, and reduced the expression of SOX2, a marker of neural stem cells, in SF188 cells. Consistent with SOX2 inhibition, the loss of PLK1 activity caused the cells to differentiate based on elevated levels of glial fibrillary acidic protein and changes in cellular morphology. We then knocked glial fibrillary acidic protein (GFAP) down SOX2 with siRNA and showed that it too inhibited cell growth and induced cell death. Likewise, in U251 cells, PLK1 inhibition suppressed cell growth, downregulated SOX2, and induced cell death. Furthermore, BI2536 delayed tumor growth of U251 cells in an orthotopic brain tumor model, demonstrating that the drug is active against GBM. In conclusion, PLK1 level is elevated in GBM and its inhibition restricts the growth of brain cancer cells.
authors.affiliation: Department of Pediatrics, Child and Family Research Institute, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Cathy
authors.initials: C
authors.lastname: Lee
authors.forename: Abbas
authors.initials: A
authors.lastname: Fotovati
authors.forename: Joanna
authors.initials: J
authors.lastname: Triscott
authors.forename: James
authors.initials: J
authors.lastname: Chen
authors.forename: Chitra
authors.initials: C
authors.lastname: Venugopal
authors.forename: Ash
authors.initials: A
authors.lastname: Singhal
authors.forename: Christopher
authors.initials: C
authors.lastname: Dunham
authors.forename: John M
authors.initials: JM
authors.lastname: Kerr
authors.forename: Maite
authors.initials: M
authors.lastname: Verreault
authors.forename: Stephen
authors.initials: S
authors.lastname: Yip
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Wakimoto
authors.forename: Chris
authors.initials: C
authors.lastname: Jones
authors.forename: Aarthi
authors.initials: A
authors.lastname: Jayanthan
authors.forename: Aru
authors.initials: A
authors.lastname: Narendran
authors.forename: Sheila K
authors.initials: SK
authors.lastname: Singh
authors.forename: Sandra E
authors.initials: SE
authors.lastname: Dunn
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D018450:Disease Progression; D005909:Glioblastoma / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D006801:Humans; D051379:Mice; D058990:Molecular Targeted Therapy; D058953:Neural Stem Cells; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011621:Pteridines / Q000494:pharmacology*; D055748:SOXB1 Transcription Factors / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D016019:Survival Analysis; D014162:Transfection; D000097869:Polo-Like Kinase 1
chemical_list: D018797:Cell Cycle Proteins; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D011621:Pteridines; D055748:SOXB1 Transcription Factors; D000097869:Polo-Like Kinase 1; C518477:BI 2536; C527783:Sox2 protein, mouse