title: Polo-like kinase 1 (PLK1) inhibition suppresses cell growth and enhances radiation sensitivity in medulloblastoma cells.
abstract: BACKGROUND
  Medulloblastoma is the most common malignant brain tumor in children and remains a therapeutic challenge due to its significant therapy-related morbidity. Polo-like kinase 1 (PLK1) is highly expressed in many cancers and regulates critical steps in mitotic progression. Recent studies suggest that targeting PLK1 with small molecule inhibitors is a promising approach to tumor therapy.
  
  
  METHODS
  We examined the expression of PLK1 mRNA in medulloblastoma tumor samples using microarray analysis. The impact of PLK1 on cell proliferation was evaluated by depleting expression with RNA interference (RNAi) or by inhibiting function with the small molecule inhibitor BI 2536. Colony formation studies were performed to examine the impact of BI 2536 on medulloblastoma cell radiosensitivity. In addition, the impact of depleting PLK1 mRNA on tumor-initiating cells was evaluated using tumor sphere assays.
  
  
  RESULTS
  Analysis of gene expression in two independent cohorts revealed that PLK1 mRNA is overexpressed in some, but not all, medulloblastoma patient samples when compared to normal cerebellum. Inhibition of PLK1 by RNAi significantly decreased medulloblastoma cell proliferation and clonogenic potential and increased cell apoptosis. Similarly, a low nanomolar concentration of BI 2536, a small molecule inhibitor of PLK1, potently inhibited cell growth, strongly suppressed the colony-forming ability, and increased cellular apoptosis of medulloblastoma cells. Furthermore, BI 2536 pretreatment sensitized medulloblastoma cells to ionizing radiation. Inhibition of PLK1 impaired tumor sphere formation of medulloblastoma cells and decreased the expression of SRY (sex determining region Y)-box 2 (SOX2) mRNA in tumor spheres indicating a possible role in targeting tumor initiating cells.
  
  
  CONCLUSIONS
  Our data suggest that targeting PLK1 with small molecule inhibitors, in combination with radiation therapy, is a novel strategy in the treatment of medulloblastoma that warrants further investigation.
authors.affiliation: Department of Pediatrics and Children's Hospital Colorado, University of Colorado Denver, Anschutz Medical Campus, Aurora, USA.
authors.forename: Peter S
authors.initials: PS
authors.lastname: Harris
authors.forename: Sujatha
authors.initials: S
authors.lastname: Venkataraman
authors.forename: Irina
authors.initials: I
authors.lastname: Alimova
authors.forename: Diane K
authors.initials: DK
authors.lastname: Birks
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Donson
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Knipstein
authors.forename: Adrian
authors.initials: A
authors.lastname: Dubuc
authors.forename: Michael D
authors.initials: MD
authors.lastname: Taylor
authors.forename: Michael H
authors.initials: MH
authors.lastname: Handler
authors.forename: Nicholas K
authors.initials: NK
authors.lastname: Foreman
authors.forename: Rajeev
authors.initials: R
authors.lastname: Vibhakar
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002528:Cerebellar Neoplasms / Q000201:enzymology / Q000473:pathology / Q000532:radiotherapy*; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D008297:Male; D008527:Medulloblastoma / Q000201:enzymology / Q000473:pathology / Q000532:radiotherapy*; D046228:Microarray Analysis; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; 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; D012313:RNA / Q000378:metabolism; D000077278:RNA, Mitochondrial; D011836:Radiation Tolerance / Q000187:drug effects*; D000097869:Polo-Like Kinase 1
chemical_list: D018797:Cell Cycle Proteins; D004791:Enzyme Inhibitors; D009363:Neoplasm Proteins; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D011621:Pteridines; D012313:RNA; D000077278:RNA, Mitochondrial; D000097869:Polo-Like Kinase 1; C518477:BI 2536