Open AccessNotch Promotes Radioresistance of Glioma Stem Cells
Author(s) -
Wang Jialiang,
Wakeman Timothy P.,
Lathia Justin D.,
Hjelmeland Anita B.,
Wang XiaoFan,
White Rebekah R.,
Rich Jeremy N.,
Sullenger Bruce A.
Publication year - 2010
Publication title -
stem cells
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.159
H-Index - 229
eISSN - 1549-4918
pISSN - 1066-5099
DOI - 10.1002/stem.261
Subject(s) - radioresistance , glioma , biology , cancer research , stem cell , notch signaling pathway , cancer stem cell , clonogenic assay , radiosensitivity , radiation therapy , signal transduction , microbiology and biotechnology , cell , medicine , cell culture , genetics
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 γ‐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. S TEM C ELLS 2010;28:17–28