Abstract
Hypoxia induces the expansion of glioblastoma stem cells (GSCs), but the mechanism underlying it is still unclear. Here, we supply evidence that hypoxia-inducible factor-1α (HIF-1α) induced activation of Notch pathway is essential for hypoxia-mediated maintenance of GSC. Either depletion of HIF-1α or inactivation of Notch signaling partly inhibits the hypoxia-mediated maintenance of GSC. Further data suggest a role for HIF-1α in the interaction and stabilization of intracellular domain of Notch (NICD), and activation of Notch signaling. The mRNA level of HIF-1α and Notch target gene FABP7 was elevated in GSC. And the STAT3 pathway responsible for the HIF-1α gene transcription, the phosphatidylinositol 3-kinase-Akt and ERK1/2, both of which are contributed to HIF-1α protein translation, are also preferentially activated in GSC. Inhibition of these pathways partly reduces the hypoxia-induced activation of the Notch pathway and subsequent GSC maintenance. Taken together, our findings suggest that HIF-1α requires Notch pathway to drive the maintenance of GSC. The activated regulation of HIF-1α makes GSC more sensitive to hypoxia-mediated maintenance. These findings enhance our understanding of mechanism of hypoxia-mediated GSC expansion and provide HIF-1α as an attractive target for glioblastoma therapy.
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Abbreviations
- U251SC:
-
U251-derived stem-like tumor sphere cells
- HIF-1α:
-
hypoxia-induced factor 1α
- GSC:
-
glioblastoma stem cell
- NICD:
-
intracellular domain of Notch
- 4E-BP1:
-
the eukaryotic translation initiation factor 4E-binding protein
- S6K:
-
p70 S6 kinase
- PI3K:
-
phosphatidylinositol 3-kinase
- MAPK:
-
mitogen-activated protein kinase
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Acknowledgements
This work was supported by the International Cooperation Program of China (No. 2008DFA32120), the National Natural Science Foundation of China (Nos. 30701032, 30472044, 90713038 and 91029744), the Natural Science Foundation of Jiangsu Province (No. BK2009297, BK2009298), and the Science and Technology Development Program supported by the division of Science and Technology, Jiangsu (No. BE2009674).
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Qiang, L., Wu, T., Zhang, HW. et al. HIF-1α is critical for hypoxia-mediated maintenance of glioblastoma stem cells by activating Notch signaling pathway. Cell Death Differ 19, 284–294 (2012). https://doi.org/10.1038/cdd.2011.95
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DOI: https://doi.org/10.1038/cdd.2011.95
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