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

Abstract

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.

Personalizing the Treatment of Pediatric Medulloblastoma: Polo-like Kinase 1 as a Molecular Target in High-Risk Children

“…None of these trials have specifically addressed the possibility that PLK1 inhibitors may be beneficial for the treatment of brain tumors. Our group has demonstrated that PLK1 inhibitors could be used to target glioblastoma (18,40) and another group has published data agreeing with our findings in medulloblastoma (41,42). We illustrate that PLK1 is a promising drug target for medulloblastoma because (i) it is highly expressed in tumors relative to normal brain tissues and (ii) there are small molecule inhibitors that suppress primary medulloblastoma cells and cell lines in vitro and in vivo.…”

Polo-like Kinase Inhibitor Ro5203280 Has Potent Antitumor Activity in Nasopharyngeal Carcinoma

“…PLK1 is the best characterized member in the PLK family, and increasing evidence suggests that PLK1 serves as a good candidate for cancer drug targeting in several malignancies; various PLK1 inhibitors are efficacious as anticancer drugs (18,32,33). A previous study showed that inhibition of PLK1 function suppresses cell growth and increases radiation sensitivity in medulloblastoma cell lines (34). In a diffuse large B-cell lymphoma study, a small-molecule PLK1 inhibitor, MLN0905, was confirmed to have antitumor effects (35).…”

In vitro targeting of Polo-like kinase 1 in bladder carcinoma

“…28,29 Synergistic effects on clonogenicity have been demonstrated in rectal tumor cells using PLK1 inhibition by siRNA combined with radiation, 26 this approach has also been effective on head-and-neck squamous cell carcinoma. 30 Comparatively, the pharmacological inhibition of PLK1 by BI 2536 has shown to radiosensitize medulloblastoma cells, 31 whereas GSK461364A-sensitized tumor cells to radiation and prevented the growth of metastatic breast cancer cells. 32 The development of drug resistance is a common problem in treatment of bladder cancers.…”