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

Childs Nerv Syst. 2012 Mar;28(3):363-73. doi: 10.1007/s00381-011-1672-x. Epub 2012 Jan 17.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AC133 Antigen
  • Animals
  • Antigens, CD / metabolism
  • Cell Differentiation / drug effects
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Cell Movement / radiation effects
  • Cell Proliferation / drug effects
  • Cell Proliferation / radiation effects
  • Cell Survival / drug effects
  • Cell Survival / radiation effects
  • Cell Transformation, Neoplastic / drug effects
  • Cell Transformation, Neoplastic / radiation effects
  • Computational Biology
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Dose-Response Relationship, Radiation
  • Glycoproteins / metabolism
  • Humans
  • Medulloblastoma / drug therapy
  • Medulloblastoma / pathology*
  • Medulloblastoma / radiotherapy
  • Mice
  • Microarray Analysis
  • Neoplastic Stem Cells / drug effects*
  • Neoplastic Stem Cells / radiation effects
  • Peptides / metabolism
  • Phosphorylation / drug effects
  • STAT3 Transcription Factor / metabolism*
  • Signal Transduction / drug effects
  • Triterpenes / pharmacology*
  • Ultraviolet Rays


  • AC133 Antigen
  • Antigens, CD
  • Glycoproteins
  • PROM1 protein, human
  • Peptides
  • Prom1 protein, mouse
  • STAT3 Transcription Factor
  • Triterpenes
  • cucurbitacin I