Polo-like kinase 1 (PLK1) inhibition suppresses cell growth and enhances radiation sensitivity in medulloblastoma cells

BMC Cancer

Research Article

Peter S Harris¹  Sujatha Venkataraman¹  Jeffrey Knipstein¹  Nicholas K Foreman¹  Andrew M Donson¹  Irina Alimova¹  Rajeev Vibhakar²  Adrian Dubuc³  Michael D Taylor³  Michael H Handler⁴  Diane K Birks⁴ 

[1] Department of Pediatrics and Children's Hospital Colorado, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA;Department of Pediatrics and Children's Hospital Colorado, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA;Department of Pediatrics, University of Colorado Denver, 12800 E 19th Ave, Mail Stop 8302, 80045, Aurora, CO, USA;Division of Neurosurgery, Program in Developmental and Stem Cell Biology, Hospital for Sick Children, Toronto, ON, Canada;Division of Pediatric Neurosurgery, Children's Hospital Colorado, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA;

关键词: Medulloblastoma;    Medulloblastoma Cell;    Tumor Sphere;    Daoy Cell;    Medulloblastoma Cell Line;   

DOI  :  10.1186/1471-2407-12-80

 received in 2011-10-06, accepted in 2012-03-05,  发布年份 2012

来源: Springer

【 摘 要 】

BackgroundMedulloblastoma 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.MethodsWe 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.ResultsAnalysis 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 inititiating cells.ConclusionsOur 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.

【 授权许可】

Unknown   
© Harris et al; licensee BioMed Central Ltd. 2012. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.