title: Expression of Notch-1 and its ligands, Delta-like-1 and Jagged-1, is critical for glioma cell survival and proliferation.
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.
authors.affiliation: Neuro-Oncology Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
authors.forename: Benjamin W
authors.initials: BW
authors.lastname: Purow
authors.forename: Raqeeb M
authors.initials: RM
authors.lastname: Haque
authors.forename: Martha W
authors.initials: MW
authors.lastname: Noel
authors.forename: Qin
authors.initials: Q
authors.lastname: Su
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Burdick
authors.forename: Jeongwu
authors.initials: J
authors.lastname: Lee
authors.forename: Tilak
authors.initials: T
authors.lastname: Sundaresan
authors.forename: Sandra
authors.initials: S
authors.lastname: Pastorino
authors.forename: John K
authors.initials: JK
authors.lastname: Park
authors.forename: Irina
authors.initials: I
authors.lastname: Mikolaenko
authors.forename: Dragan
authors.initials: D
authors.lastname: Maric
authors.forename: Charles G
authors.initials: CG
authors.lastname: Eberhart
authors.forename: Howard A
authors.initials: HA
authors.lastname: Fine
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D002135:Calcium-Binding Proteins; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000502:physiology; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D005910:Glioma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D006023:Glycoproteins / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D000072100:Jagged-1 Protein; D008024:Ligands; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D009368:Neoplasm Transplantation; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D051881:Receptor, Notch1; D011956:Receptors, Cell Surface / Q000096:biosynthesis* / Q000235:genetics; D000072099:Serrate-Jagged Proteins; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics; D014183:Transplantation, Heterologous
chemical_list: D002135:Calcium-Binding Proteins; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; C000606273:JAG1 protein, human; C000606274:Jag1 protein, mouse; D000072100:Jagged-1 Protein; D008024:Ligands; D008565:Membrane Proteins; C497761:NOTCH1 protein, human; C497762:Notch1 protein, mouse; D034741:RNA, Small Interfering; D051881:Receptor, Notch1; D011956:Receptors, Cell Surface; D000072099:Serrate-Jagged Proteins; D014157:Transcription Factors