Journal
STEM CELLS
Volume 28, Issue 1, Pages 17-28Publisher
ALPHAMED PRESS
DOI: 10.1002/stem.261
Keywords
Notch; Cancer stem cells; Glioma; Radioresistance; Radioresponse
Categories
Funding
- American Brain Tumor Association
- National Service Research [NCI F32 CA142159]
- National Institutes of Health (NIH) [CA129190]
- Childhood Brain Tumor Foundation
- Pediatric Brain Tumor Foundation
- Accelerate Brain Cancer Cure
- Alexander and Margaret Stewart Trust
- Brain Tumor Society
- Goldhirsh Foundation
- Sidney Kimmel Foundation
- Damon Runyon Cancer Research Foundation
- NIH [NS047409, NS054276, CA129958, CA116659]
- NATIONAL CANCER INSTITUTE [F32CA142159, R01CA129958, R01CA116659, R01CA129190] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [K02NS047409, R01NS054276] Funding Source: NIH RePORTER
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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. STEM CELLS 2010; 28: 17-28
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