Notch promotes radioresistance of glioma stem cells.

Wang J, Wakeman TP, Lathia JD, Hjelmeland AB, Wang XF, White RR, Rich JN, Sullenger BA
Stem Cells. 2010 28 (1): 17-28

PMID: 19921751 · PMCID: PMC2825687 · DOI:10.1002/stem.261

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.

MeSH Terms (32)

AC133 Antigen Amyloid Precursor Protein Secretases Animals Antigens, CD Cell Death Cell Proliferation Cell Survival Dose-Response Relationship, Radiation Enzyme Inhibitors Glioblastoma Glycoproteins Humans Mice Mice, Nude Myeloid Cell Leukemia Sequence 1 Protein Neoplastic Stem Cells Peptides Phosphatidylinositol 3-Kinases Proto-Oncogene Proteins c-akt Proto-Oncogene Proteins c-bcl-2 Radiation-Sensitizing Agents Radiation Tolerance Receptor, Notch1 Receptor, Notch2 RNA Interference Signal Transduction Spheroids, Cellular Time Factors Transfection Tumor Burden Tumor Cells, Cultured Xenograft Model Antitumor Assays

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