STAT3 is required for proliferation and maintenance of multipotency in glioblastoma stem cells

Stem Cells. 2009 Oct;27(10):2383-92. doi: 10.1002/stem.185.


Signal transducer and activator of transcription 3 (STAT3) regulates diverse cellular processes, including cell growth, differentiation, and apoptosis, and is frequently activated during tumorigenesis. Recently, putative glioblastoma stem cells (GBM-SCs) were isolated and characterized. These cells can self-renew indefinitely in culture, are highly tumorigenic, and retain the ability to differentiate in culture. We have found that treatment of GBM-SCs with two chemically distinct small molecule inhibitors of STAT3 DNA-binding inhibits cell proliferation and the formation of new neurospheres from single cells. Genetic knockdown of STAT3 using a short hairpin RNA also inhibits GBM-SC proliferation and neurosphere formation, confirming that these effects are specific to STAT3. Although STAT3 inhibition can induce apoptosis in serum-derived GBM cell lines, this effect was not observed in GBM-SCs grown in stem cell medium. Markers of neural stem cell multipotency also decrease upon STAT3 inhibition, suggesting that STAT3 is required for maintenance of the stem-like characteristics of these cells. Strikingly, even a transient inhibition of STAT3 leads to irreversible growth arrest and inhibition of neurosphere formation. These data suggest that STAT3 regulates the growth and self-renewal of GBM-SCs and is thus a potential target for cancer stem cell-directed therapy of glioblastoma multiforme.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged, 80 and over
  • Brain Neoplasms / drug therapy
  • Brain Neoplasms / genetics
  • Brain Neoplasms / metabolism*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Culture Media / pharmacology
  • Down-Regulation / genetics
  • Female
  • Glioblastoma / drug therapy
  • Glioblastoma / genetics
  • Glioblastoma / metabolism*
  • Growth Inhibitors / metabolism
  • Humans
  • Inhibitor of Differentiation Protein 1 / pharmacology
  • Male
  • Multipotent Stem Cells / drug effects
  • Multipotent Stem Cells / metabolism*
  • Neoplastic Stem Cells / drug effects
  • Neoplastic Stem Cells / metabolism*
  • RNA Interference / physiology
  • STAT3 Transcription Factor / genetics*
  • STAT3 Transcription Factor / metabolism*
  • Spheroids, Cellular / drug effects
  • Spheroids, Cellular / metabolism


  • Culture Media
  • Growth Inhibitors
  • Inhibitor of Differentiation Protein 1
  • STAT3 Transcription Factor
  • STAT3 protein, human