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Inhibition of phosphorylated STAT3 by cucurbitacin I enhances chemoradiosensitivity in medulloblastoma-derived cancer stem cells

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Abstract

Introduction

CD133 (PROM1) is a potential marker for cancer stem cells (CSCs), including those found in brain tumors. Recently, medulloblastoma (MB)-derived CD133-positive cells were found to have CSC-like properties and were proposed to be important contributors to tumorigenicity, cancer progression, and chemoradioresistance. However, the biomolecular pathways and therapeutic targets specific to MB-derived CSCs remain unresolved.

Materials and methods

In the present study, we isolated CD133+ cells from MB cell lines and determined that they showed increased tumorigenicity, radioresistance, and higher expression of both embryonic stem cell-related and drug resistance-related genes compared to CD133 cells. Bioinformatics analysis suggested that the STAT3 pathway might be important in MB and CD133+ cells. To evaluate the effects of inhibiting the STAT3 pathway, MB-derived CD133+/− cells were treated with the potent STAT3 inhibitor, cucurbitacin I. Treatment with cucurbitacin I significantly suppressed the CSC-like properties and stemness gene signature of MB-derived CD133+ cells. Furthermore, cucurbitacin I treatment increased the apoptotic sensitivity of MB-derived CD133+ cells to radiation and chemotherapeutic drugs. Notably, cucurbitacin I demonstrated synergistic effects with ionizing radiation to inhibit tumorigenicity in MB-CD133+-inoculated mice.

Results

These results indicate that the STAT3 pathway plays a key role in mediating CSC properties in MB-derived CD133+ cells. Targeting STAT3 with cucurbitacin I may therefore represent a novel therapeutic approach for treating malignant brain tumors.

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Acknowledgments

This study was supported by research grants from the National Science Council (NSC-98-3111-B-075-001-MY3), the Yen-Tjing-Ling Medical Foundation (98/99/100),Chi Mei Medical Center (CMYM 9801/9901/100001), Taipei City Hospital (98/99/100), and Cheng-Hsin General Hospital (98/99/100).

Author information

Correspondence to Ming-Chi Yung or Kai-Hsi Lu.

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Chang, C., Chiang, C., Song, W. et al. Inhibition of phosphorylated STAT3 by cucurbitacin I enhances chemoradiosensitivity in medulloblastoma-derived cancer stem cells. Childs Nerv Syst 28, 363–373 (2012). https://doi.org/10.1007/s00381-011-1672-x

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Keywords

  • Medulloblastoma
  • Cucurbitacin I
  • Cancer stem cells
  • CD133
  • STAT3
  • Radioresistance