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Notch promotes radioresistance of glioma stem cells.

Publication ,  Journal Article
Wang, J; Wakeman, TP; Lathia, JD; Hjelmeland, AB; Wang, X-F; White, RR; Rich, JN; Sullenger, BA
Published in: Stem Cells
January 2010

Radiotherapy represents the most effective nonsurgical treatments for gliomas. However, gliomas are highly radioresistant and recurrence is nearly universal. Results from our laboratory and other groups suggest that cancer stem cells contribute to radioresistance in gliomas and breast cancers. The Notch pathway is critically implicated in stem cell fate determination and cancer. In this study, we show that inhibition of Notch pathway with gamma-secretase inhibitors (GSIs) renders the glioma stem cells more sensitive to radiation at clinically relevant doses. GSIs enhance radiation-induced cell death and impair clonogenic survival of glioma stem cells but not non-stem glioma cells. Expression of the constitutively active intracellular domains of Notch1 or Notch2 protect glioma stem cells against radiation. Notch inhibition with GSIs does not alter the DNA damage response of glioma stem cells after radiation but rather reduces Akt activity and Mcl-1 levels. Finally, knockdown of Notch1 or Notch2 sensitizes glioma stem cells to radiation and impairs xenograft tumor formation. Taken together, our results suggest a critical role of Notch signaling to regulate radioresistance of glioma stem cells. Inhibition of Notch signaling holds promise to improve the efficiency of current radiotherapy in glioma treatment.

Duke Scholars

Published In

Stem Cells

DOI

EISSN

1549-4918

Publication Date

January 2010

Volume

28

Issue

1

Start / End Page

17 / 28

Location

England

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • Tumor Cells, Cultured
  • Tumor Burden
  • Transfection
  • Time Factors
  • Spheroids, Cellular
  • Signal Transduction
  • Receptor, Notch2
  • Receptor, Notch1
  • Radiation-Sensitizing Agents
 

Citation

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Wang, J., Wakeman, T. P., Lathia, J. D., Hjelmeland, A. B., Wang, X.-F., White, R. R., … Sullenger, B. A. (2010). Notch promotes radioresistance of glioma stem cells. Stem Cells, 28(1), 17–28. https://doi.org/10.1002/stem.261
Wang, Jialiang, Timothy P. Wakeman, Justin D. Lathia, Anita B. Hjelmeland, Xiao-Fan Wang, Rebekah R. White, Jeremy N. Rich, and Bruce A. Sullenger. “Notch promotes radioresistance of glioma stem cells.Stem Cells 28, no. 1 (January 2010): 17–28. https://doi.org/10.1002/stem.261.
Wang J, Wakeman TP, Lathia JD, Hjelmeland AB, Wang X-F, White RR, et al. Notch promotes radioresistance of glioma stem cells. Stem Cells. 2010 Jan;28(1):17–28.
Wang, Jialiang, et al. “Notch promotes radioresistance of glioma stem cells.Stem Cells, vol. 28, no. 1, Jan. 2010, pp. 17–28. Pubmed, doi:10.1002/stem.261.
Wang J, Wakeman TP, Lathia JD, Hjelmeland AB, Wang X-F, White RR, Rich JN, Sullenger BA. Notch promotes radioresistance of glioma stem cells. Stem Cells. 2010 Jan;28(1):17–28.
Journal cover image

Published In

Stem Cells

DOI

EISSN

1549-4918

Publication Date

January 2010

Volume

28

Issue

1

Start / End Page

17 / 28

Location

England

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • Tumor Cells, Cultured
  • Tumor Burden
  • Transfection
  • Time Factors
  • Spheroids, Cellular
  • Signal Transduction
  • Receptor, Notch2
  • Receptor, Notch1
  • Radiation-Sensitizing Agents