Notch Promotes Radioresistance of Glioma Stem Cells
By Jialiang Wang, T. Wakeman, Justin D. Latha, Anita B. Hjelmeland, Xiao-Fan Wang, R. R. White, Jeremy N. Rich, Bruce A. Sullenger. Stem Cells, 2009
665 citations recorded by the source corpus.
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. STEM CELLS 2010;28:17–28
Subfields: Cancer Research, Molecular Biology
View Paper: https://www.semanticscholar.org/paper/98b8d7a097bf0c0ea84726e184c407fe490a3d22
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Citations in the corpus
- Cancer stem cells in glioblastoma (2015, background): “The importance of Notch signaling in glioma CSC biology is highlighted by the convergence on this pathway from other pathways and exogenous factors, such as hypoxia, eNOS signaling, and response to radiation (Charles et al. 2010; Wang et al. 2010; Qiang et al. 2012).”
- Cancer Stem Cells (CSCs) in Drug Resistance and their Therapeutic Implications in Cancer Treatment (2018, background): “Notch pathway also promotes the radioresistance of glioma stem cells as the Notch inhibition with gamma-secretase inhibitors (GSIs) induces the glioma stem cells to be more sensitive to radiation at clinically relevant doses due to the reduction of radiation-induced PI3K/Akt activation and upregulat”
- Targeting cancer stem cell pathways for cancer therapy (2020, background): “18 In addition, other signaling molecules, such as PTEN and the polycomb family, also play important roles in the regulation of CSC growth.”