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 further along these same pathways. Retinoic acid and forskolin induce a neuronal phenotype, denoted morphologically by cell aggregation and increased neurite formation and biochemically by increases in neurofilament proteins, tyrosine hydroxylase, and secretogranin II and decrease in chromogranin 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.
Document Type: Research Article
Affiliations: 1: *Department of Biological Sciences, Fordham University, Bronx, NY 10458 2: †Department of Pharmacology and Comparative Medicine, University of South Alabama College of Medicine, Mobile, AL 36688
Publication date: 2002-02-01
- Formerly: Oncology Research Incorporating Anti-Cancer Drug Design
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