Abstract
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.
MeSH terms
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Amino Acid Sequence
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Animals
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Brain Neoplasms / genetics
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Brain Neoplasms / metabolism*
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Brain Neoplasms / pathology*
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Calcium-Binding Proteins
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Cell Growth Processes / physiology
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Cell Line, Tumor
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Cell Survival / physiology
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Down-Regulation
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Gene Expression Regulation, Neoplastic
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Glioma / genetics
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Glioma / metabolism*
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Glioma / pathology*
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Glycoproteins / biosynthesis*
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Glycoproteins / genetics
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Humans
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Intercellular Signaling Peptides and Proteins
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Jagged-1 Protein
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Ligands
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Membrane Proteins / biosynthesis*
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Membrane Proteins / genetics
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Mice
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Neoplasm Transplantation
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RNA Interference
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RNA, Small Interfering / genetics
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Receptor, Notch1
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Receptors, Cell Surface / biosynthesis*
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Receptors, Cell Surface / genetics
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Serrate-Jagged Proteins
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Transcription Factors / biosynthesis*
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Transcription Factors / genetics
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Transplantation, Heterologous
Substances
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Calcium-Binding Proteins
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Glycoproteins
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Intercellular Signaling Peptides and Proteins
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JAG1 protein, human
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Jag1 protein, mouse
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Jagged-1 Protein
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Ligands
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Membrane Proteins
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NOTCH1 protein, human
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Notch1 protein, mouse
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RNA, Small Interfering
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Receptor, Notch1
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Receptors, Cell Surface
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Serrate-Jagged Proteins
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Transcription Factors