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[Cancer Research 65, 2353-2363, March 15, 2005]
© 2005 American Association for Cancer Research

Experimental Therapeutics, Molecular Targets, and Chemical Biology

Expression of Notch-1 and Its Ligands, Delta-Like-1 and Jagged-1, Is Critical for Glioma Cell Survival and Proliferation

Benjamin W. Purow1,2, Raqeeb M. Haque1,2, Martha W. Noel1,2, Qin Su1,2, Michael J. Burdick1,2, Jeongwu Lee1,2, Tilak Sundaresan1,2, Sandra Pastorino1,2, John K. Park2, Irina Mikolaenko3, Dragan Maric2, Charles G. Eberhart3 and Howard A. Fine1,2

1 Neuro-Oncology Branch, National Cancer Institute and 2 National Institute of Neurological Disorders and Stroke, NIH, Bethesda, Maryland; and 3 Pathology Department, Johns Hopkins School of Medicine, Baltimore, Maryland

Requests for reprints: Howard A. Fine, Neuro-Oncology Branch, National Cancer Institute/National Institute of Neurological Disorders and Stroke, NIH, Room 225 Building 82, Bloch Building, 9030 Old Georgetown Road, Bethesda, MD 20892. Phone: 301-402-6298; Fax: 301-480-2246; E-mail: hfine{at}mail.nih.gov.

The Notch family of proteins plays an integral role in determining cell fates, such as proliferation, differentiation, and apoptosis. We show that Notch-1 and its ligands, Delta-like-1 and Jagged-1, are overexpressed in many glioma cell lines and primary human gliomas. Immunohistochemistry of a primary human glioma tissue array shows the presence in the nucleus of the Notch-1 intracellular domain, indicating Notch-1 activation in situ. Down-regulation of Notch-1, Delta-like-1, or Jagged-1 by RNA interference induces apoptosis and inhibits proliferation in multiple glioma cell lines. In addition, pretreatment of glioma cells with Notch-1 or Delta-like-1 small interfering RNA significantly prolongs survival in a murine orthotopic brain tumor model. These results show, for the first time, the dependence of cancer cells on a single Notch ligand; they also suggest a potential Notch juxtacrine/autocrine loop in gliomas. Notch-1 and its ligands may present novel therapeutic targets in the treatment of glioma.

Key Words: Notch • Delta-like • Jagged • glioma • neuro-oncology




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Copyright © 2005 by the American Association for Cancer Research.