PMID- 19921751
OWN - NLM
STAT- MEDLINE
DCOM- 20100301
LR  - 20220311
IS  - 1549-4918 (Electronic)
IS  - 1066-5099 (Print)
IS  - 1066-5099 (Linking)
VI  - 28
IP  - 1
DP  - 2010 Jan
TI  - Notch promotes radioresistance of glioma stem cells.
PG  - 17-28
LID - 10.1002/stem.261 [doi]
AB  - 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.
FAU - Wang, Jialiang
AU  - Wang J
AD  - Department of Surgery, Duke University Medical Center, Durham, North Carolina, 
      USA. jialiang.wang@duke.edu
FAU - Wakeman, Timothy P
AU  - Wakeman TP
FAU - Lathia, Justin D
AU  - Lathia JD
FAU - Hjelmeland, Anita B
AU  - Hjelmeland AB
FAU - Wang, Xiao-Fan
AU  - Wang XF
FAU - White, Rebekah R
AU  - White RR
FAU - Rich, Jeremy N
AU  - Rich JN
FAU - Sullenger, Bruce A
AU  - Sullenger BA
LA  - eng
GR  - NS054276/NS/NINDS NIH HHS/United States
GR  - R01 CA116659/CA/NCI NIH HHS/United States
GR  - R01 NS054276-03/NS/NINDS NIH HHS/United States
GR  - F32 CA142159/CA/NCI NIH HHS/United States
GR  - R01 CA116659-05/CA/NCI NIH HHS/United States
GR  - HHMI/Howard Hughes Medical Institute/United States
GR  - CA129958/CA/NCI NIH HHS/United States
GR  - R01 CA116659-04/CA/NCI NIH HHS/United States
GR  - CA116659/CA/NCI NIH HHS/United States
GR  - NS047409/NS/NINDS NIH HHS/United States
GR  - R01 CA129958/CA/NCI NIH HHS/United States
GR  - R01 CA129190-01A2/CA/NCI NIH HHS/United States
GR  - R01 CA129958-02/CA/NCI NIH HHS/United States
GR  - R01 CA129190/CA/NCI NIH HHS/United States
GR  - R01 NS054276/NS/NINDS NIH HHS/United States
GR  - R01 CA129958-01A1/CA/NCI NIH HHS/United States
GR  - R01 NS054276-04/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Stem Cells
JT  - Stem cells (Dayton, Ohio)
JID - 9304532
RN  - 0 (AC133 Antigen)
RN  - 0 (Antigens, CD)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Glycoproteins)
RN  - 0 (Mcl1 protein, mouse)
RN  - 0 (Myeloid Cell Leukemia Sequence 1 Protein)
RN  - 0 (Peptides)
RN  - 0 (Proto-Oncogene Proteins c-bcl-2)
RN  - 0 (Radiation-Sensitizing Agents)
RN  - 0 (Receptor, Notch1)
RN  - 0 (Receptor, Notch2)
RN  - EC 2.7.1.- (Phosphatidylinositol 3-Kinases)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 3.4.- (Amyloid Precursor Protein Secretases)
SB  - IM
MH  - AC133 Antigen
MH  - Amyloid Precursor Protein Secretases/antagonists & inhibitors/metabolism
MH  - Animals
MH  - Antigens, CD/metabolism
MH  - Cell Death
MH  - Cell Proliferation
MH  - Cell Survival
MH  - Dose-Response Relationship, Radiation
MH  - Enzyme Inhibitors/pharmacology
MH  - Glioblastoma/drug therapy/metabolism/pathology/*radiotherapy
MH  - Glycoproteins/metabolism
MH  - Humans
MH  - Mice
MH  - Mice, Nude
MH  - Myeloid Cell Leukemia Sequence 1 Protein
MH  - Neoplastic Stem Cells/drug effects/metabolism/pathology/*radiation effects
MH  - Peptides/metabolism
MH  - Phosphatidylinositol 3-Kinases/metabolism
MH  - Proto-Oncogene Proteins c-akt/metabolism
MH  - Proto-Oncogene Proteins c-bcl-2/metabolism
MH  - RNA Interference
MH  - *Radiation Tolerance/drug effects
MH  - Radiation-Sensitizing Agents/pharmacology
MH  - Receptor, Notch1/genetics/*metabolism
MH  - Receptor, Notch2/genetics/*metabolism
MH  - Signal Transduction/radiation effects
MH  - Spheroids, Cellular
MH  - Time Factors
MH  - Transfection
MH  - Tumor Burden
MH  - Tumor Cells, Cultured
MH  - Xenograft Model Antitumor Assays
PMC - PMC2825687
MID - NIHMS165162
EDAT- 2009/11/19 06:00
MHDA- 2010/03/02 06:00
PMCR- 2011/01/01
CRDT- 2009/11/19 06:00
PHST- 2009/11/19 06:00 [entrez]
PHST- 2009/11/19 06:00 [pubmed]
PHST- 2010/03/02 06:00 [medline]
PHST- 2011/01/01 00:00 [pmc-release]
AID - 10.1002/stem.261 [doi]
PST - ppublish
SO  - Stem Cells. 2010 Jan;28(1):17-28. doi: 10.1002/stem.261.