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

Charn Jung Chang, Chih Hung Chiang, Wen Shin Song, Shen Kou Tsai, Lin Chung Woung, Chin Hong Chang, Shaw Yeu Jeng, Ching Yao Tsai, Chuan Chih Hsu, Hung Fu Lee, Chi Shuan Huang, Ming Chi Yung, Jorn Hon Liu, Kai Hsi Lu

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27 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)363-373
Number of pages11
JournalChild's Nervous System
Volume28
Issue number3
DOIs
Publication statusPublished - 2012
Externally publishedYes

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Keywords

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

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health
  • Clinical Neurology
  • Medicine(all)

Cite this

Chang, C. J., Chiang, C. H., Song, W. S., Tsai, S. K., Woung, L. C., Chang, C. H., Jeng, S. Y., Tsai, C. Y., Hsu, C. C., Lee, H. F., Huang, C. S., Yung, M. C., Liu, J. H., & Lu, K. H. (2012). Inhibition of phosphorylated STAT3 by cucurbitacin I enhances chemoradiosensitivity in medulloblastoma-derived cancer stem cells. Child's Nervous System, 28(3), 363-373. https://doi.org/10.1007/s00381-011-1672-x