title: Glucocorticoids induce neuroendocrine cell differentiation and increase expression of N-myc in N-type human neuroblastoma cells.
abstract: Human neuroblastoma cell lines comprise cellular counterparts of normal differentiation phenotypes arising from the developing neural crest Three distinct cell types have been isolated from cell lines: N-type cells with properties of embryonic sympathoadrenoblasts, S-type cells resembling nonneuronal Schwannian/glial/melanoblastic precursors, and I-type stem cells that can differentiate into either N- or S-type cells. Sympathoadrenoblasts from the normal neural crest further differentiate into neuronal or neuroendocrine cells. In this study, we show that malignant N-type neuroblasts likewise can differentiate futher along these same pathways. Retinoic acid and forskolin induce a neuronalphenotype, denoted morphologically by cell aggregation and increased neurite formation and biochemically by increases in neurofilament proteins, tyrosine hydroxylase, and secretogranin II and decrease inchromogranin A. By contrast, dexamethasone, a synthetic glucocorticoid, induces a chromaffin cell phenotype characterized by increased cell flattening, loss of neuritic processes, increased chromogranin A and tyrosine hydroxylase proteins, and decreased amounts of secretogranin II and neurofilaments. N-myc gene expression is upregulated by glucocorticoids; dexamethasone-treated N-type cells show significant (2.3- to 7.8-fold) increases in N-myc mRNA and protein steady-state levels. This effect is specific for glucocorticosteroids, is blocked by addition of the steroid receptor antagonist RU486, and involves direct activation of the N-myc promoter. These findings are the first to show that glucocorticoids upregulate N-myc expression in human neuroblastoma cells.
authors.affiliation: Department of Biological Sciences, Fordham University, Bronx, NY 10458, USA. rross@fordham.edu
authors.forename: Robert A
authors.initials: RA
authors.lastname: Ross
authors.forename: Anne M
authors.initials: AM
authors.lastname: Hein
authors.forename: John A
authors.initials: JA
authors.lastname: Braca
authors.forename: Barbara A
authors.initials: BA
authors.lastname: Spengler
authors.forename: June L
authors.initials: JL
authors.lastname: Biedler
authors.forename: Jonathan G
authors.initials: JG
authors.lastname: Scammell
mesh_terms: D002454:Cell Differentiation / Q000187:drug effects; D019439:Chromaffin Cells / Q000166:cytology / Q000187:drug effects; D003907:Dexamethasone / Q000494:pharmacology*; D016259:Genes, myc; D006801:Humans; D015735:Mifepristone / Q000494:pharmacology; D009447:Neuroblastoma / Q000473:pathology*; D009490:Neurosecretory Systems / Q000166:cytology / Q000187:drug effects*; D011401:Promoter Regions, Genetic; D016271:Proto-Oncogene Proteins c-myc / Q000032:analysis / Q000096:biosynthesis* / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis
chemical_list: D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D015735:Mifepristone; D003907:Dexamethasone