Conservation of the Notch1 signaling pathway in gastrointestinal carcinoid cells.
Gastrointestinal (GI) carcinoid cells secrete multiple neuroendocrine (NE) markers and hormones including 5-hydroxytryptamine and chromogranin A. We were interested in determining whether activation of the Notch1 signal transduction pathway in carcinoid cells could modulate production of NE markers and hormones. Human pancreatic carcinoid cells (BON cells) were stably transduced with an estrogen-inducible Notch1 construct, creating BON-NIER cells. In the present study, we found that Notch1 is not detectable in human GI carcinoid tumor cells. The induction of Notch1 in human BON carcinoid cells led to high levels of functional Notch1, as measured by CBF-1 binding studies, resulting in activation of the Notch1 pathway. Similar to its developmental role in the GI tract, Notch1 pathway activation led to an increase in hairy enhancer of split 1 (HES-1) protein and a concomitant silencing of human Notch1/HES-1/achaete-scute homolog 1. Furthermore, Notch1 activation led to a significant reduction in NE markers. Most interestingly, activation of the Notch1 pathway caused a significant reduction in 5-hydroxytryptamine, an important bioactive hormone in carcinoid syndrome. In addition, persistent activation of the Notch1 pathway in BON cells led to a notable reduction in cellular proliferation. These results demonstrate that the Notch1 pathway, which plays a critical role in the differentiation of enteroendocrine cells, is highly conserved in the gut. Therefore, manipulation of the Notch1 signaling pathway may be useful for expanding the targets for therapeutic and palliative treatment of patients with carcinoid tumors.
Kunnimalaiyaan
Muthusamy
M
Dept. of Surgery, University of Wisconsin Medical School, Madison, WI 53792, USA.
Traeger
Kelly
K
Chen
Herbert
H
D051792:Basic Helix-Loop-Helix Proteins; D015153:Blotting, Western; D002276:Carcinoid Tumor / Q000473:pathology / Q000503:physiopathology*; D045744:Cell Line, Tumor; D053379:Chromogranin A; D002864:Chromogranins / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D005770:Gastrointestinal Neoplasms / Q000473:pathology / Q000503:physiopathology*; D017930:Genes, Reporter; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; D008156:Luciferases / Q000235:genetics; D009687:Nuclear Proteins / Q000378:metabolism; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D051881:Receptor, Notch1; D011956:Receptors, Cell Surface / Q000096:biosynthesis* / Q000235:genetics; D012701:Serotonin / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D016708:Synaptophysin / Q000378:metabolism; D000072056:Transcription Factor HES-1; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism
D051792:Basic Helix-Loop-Helix Proteins; D053379:Chromogranin A; D002864:Chromogranins; D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; D008156:Luciferases; D009687:Nuclear Proteins; D010751:Phosphopyruvate Hydratase; D051881:Receptor, Notch1; D011956:Receptors, Cell Surface; D012701:Serotonin; D016708:Synaptophysin; D000072056:Transcription Factor HES-1; D014157:Transcription Factors; C065500:ASCL1 protein, human; C497761:NOTCH1 protein, human; C497570:RBPJ protein, human; C078493:HES1 protein, human