title: Dominant-negative Notch3 receptor inhibits mitogen-activated protein kinase pathway and the growth of human lung cancers.
abstract: Notch3 is a member of an evolutionarily conserved family of cell surface receptors important in cell-fate determination in both vertebrates and invertebrates. Significant data support the role of Notch pathway in cancer development, although the conflicting role of Notch signaling pathways in tumorigenesis suggests that its action is highly context-dependent. Furthermore, although Notch receptors signal primarily through the regulation of hairy enhancer of split (HES) and HES-related (HRT) genes, they are known to crosstalk with other signaling pathways, including the epidermal growth factor (EGF) and the mitogen-activated protein kinase pathways. Whereas much is known about the role of Notch1 in human cancer, the role of Notch3 in epithelial tumors, such as lung carcinomas, has not been well established. In this study, we show that Notch3 is expressed in 80 of 207 (39%) resected human lung tumors and that its expression is positively correlated with EGF receptor expression. Inhibition of the Notch3 pathway using a dominant-negative receptor dramatically reduces growth in soft agar and increases growth factor dependence. We also find that Notch inhibition increases sensitivity to EGF receptor tyrosine kinase inhibition and decrease in phosphorylation of the mitogen-activated protein kinase. These observations support a role for Notch3 signaling in lung cancer, and one potential mechanism of maintaining the neoplastic phenotype is through the modulation of the EGF pathway.
authors.affiliation: Division of Hematology, Allergy/Pulmonary and Critical Care Medicine, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA.
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Haruki
authors.forename: Keiko S
authors.initials: KS
authors.lastname: Kawaguchi
authors.forename: Shannon
authors.initials: S
authors.lastname: Eichenberger
authors.forename: Pierre P
authors.initials: PP
authors.lastname: Massion
authors.forename: Sandra
authors.initials: S
authors.lastname: Olson
authors.forename: Adriana
authors.initials: A
authors.lastname: Gonzalez
authors.forename: David P
authors.initials: DP
authors.lastname: Carbone
authors.forename: Thao P
authors.initials: TP
authors.lastname: Dang
mesh_terms: D017209:Apoptosis / Q000502:physiology; D018797:Cell Cycle Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D015536:Down-Regulation; D054638:Dual Specificity Phosphatase 1; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D017874:Immediate-Early Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D008175:Lung Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D020935:MAP Kinase Signaling System / Q000502:physiology*; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010749:Phosphoprotein Phosphatases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D054645:Protein Phosphatase 1; D017027:Protein Tyrosine Phosphatases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D011799:Quinazolines; D000071656:Receptor, Notch3; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D051880:Receptors, Notch; D014162:Transfection; D020032:Tyrphostins / Q000494:pharmacology
chemical_list: D018797:Cell Cycle Proteins; D004791:Enzyme Inhibitors; D017874:Immediate-Early Proteins; C499374:NOTCH3 protein, human; D011518:Proto-Oncogene Proteins; D011799:Quinazolines; D000071656:Receptor, Notch3; D011956:Receptors, Cell Surface; D051880:Receptors, Notch; D020032:Tyrphostins; C101044:RTKI cpd; D066246:ErbB Receptors; D020928:Mitogen-Activated Protein Kinases; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1; C517019:DUSP1 protein, human; D054638:Dual Specificity Phosphatase 1; D017027:Protein Tyrosine Phosphatases