Cancer Stem Cells

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Notch Promotes Radioresistance of Glioma Stem Cells†‡§

  1. Jialiang Wang1,2,¶,*,
  2. Timothy P. Wakeman3,
  3. Justin D. Lathia4,
  4. Anita B. Hjelmeland4,
  5. Xiao-Fan Wang3,
  6. Rebekah R. White1,2,
  7. Jeremy N. Rich4,‖,*,
  8. Bruce A. Sullenger1,2,††,*

Article first published online: 17 NOV 2009

DOI: 10.1002/stem.261

Issue

STEM CELLS

STEM CELLS

Volume 28, Issue 1, pages 17–28, January 2010

Additional Information

How to Cite

Wang, J., Wakeman, T. P., Lathia, J. D., Hjelmeland, A. B., Wang, X.-F., White, R. R., Rich, J. N. and Sullenger, B. A. (2010), Notch Promotes Radioresistance of Glioma Stem Cells. STEM CELLS, 28: 17–28. doi: 10.1002/stem.261

Author Information

  1. 1

    Department of Surgery,Duke University Medical Center, Durham, North Carolina

  2. 2

    Duke Translational Research Institute,Duke University Medical Center, Durham, North Carolina

  3. 3

    Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina

  4. 4

    Department of Stem Cell Biology and Regenerative Medicine, Cleveland Clinic, Cleveland, Ohio

  1. Telephone: 919-684-4822; Fax: 919-684-8492

  2. ‖

    Telephone: 216-636-0790; Fax: 216-636-5454

  3. ††

    Telephone: 919-684-6375; Fax: 919-684-8492

*Box 103035, 1045 MSRB II, 106 Research Drive, Durham, NC 27710

  1. †

    Author contributions: J.W.: Conception and design, financial support, collection and/or assembly of data, data analysis and interpretation, manuscript writing, final approval of manuscript; T.P.W.: Collection and/or assembly of data; J.D.L.: Collection and/or assembly of data; A.B.H.: Collection and/or assembly of data, data analysis and interpretation; X.-F.W.: Financial support; R.R.W.: Financial support; J.N.R.: Financial support, conception and design, manuscript writing, final approval of manuscript; B.A.S.: Financial support, conception and design, manuscript writing, final approval of manuscript.

  2. ‡

    Disclosure of potential conflicts of interest is found at the end of this article.

  3. §

    First published online in STEM CELLS EXPRESS November 17, 2009.

Publication History

  1. Issue published online: 12 JAN 2010
  2. Article first published online: 17 NOV 2009
  3. Accepted manuscript online: 17 NOV 2009 12:00AM EST
  4. Manuscript Accepted: 6 NOV 2009
  5. Manuscript Received: 17 AUG 2009

Funded by

  • Basic Research Fellowship from the American Brain Tumor Association
  • Howard Hughes Medical Institute Early Career Award
  • Basic Research Fellowship from the American Brain Tumor Association
  • National Service Research Award. Grant Number: NCI F32 CA142159
  • National Institutes of Health (NIH). Grant Number: CA129190
  • Childhood Brain Tumor Foundation
  • Pediatric Brain Tumor Foundation of the United States
  • Accelerate Brain Cancer Cure
  • Alexander and Margaret Stewart Trust
  • Brain Tumor Society
  • Goldhirsh Foundation
  • Sidney Kimmel Foundation
  • Damon Runyon Cancer Research Foundation
  • NIH grants. Grant Numbers: NS047409, NS054276, CA129958, CA116659

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Keywords:

  • Notch;
  • Cancer stem cells;
  • Glioma;
  • Radioresistance;
  • Radioresponse

Abstract

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

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