title: Dehydroepiandrosterone-sulphate (DHEA-S) promotes neuroendocrine differentiation of chromaffin pheochromocytoma PC12 cells.
abstract: The major source for dehydroepiandrosterone (DHEA) and its sulphate compound DHEA-S is the inner zone of the adrenal cortex, which is in direct contact to adrenomedullary chromaffin cells. Due to their close proximity, direct interactions of DHEA and DHEA-S with chromaffin cells during adrenal gland development and throughout the whole life span are hypothesized. A possible direct effect of DHEA-S and the cellular and molecular mechanisms of DHEA-S action on chromaffin cells remain unresolved. Therefore, in this study, we aimed at clarifying DHEA-S effects and mechanisms of action on rat chromaffin PC12 cells. DHEA-S (10(-6)mol/l) inhibited nerve growth factor (NGF, 20ng/ml)-induced cell proliferation by 66% (n=4, p<0.001). In NGF-stimulated cells, neuronal differentiation was inhibited by DHEA-S, as demonstrated by a 22% reduction (n=3; p<0.05) of neuronal differentiation marker expression, synaptosome-associated protein of 25kDa (SNAP-25), and a 59% (n=6; p<0.001) decrease in neurite outgrowth. Moreover, DHEA-S stimulated expression of endocrine marker chromogranin A (CgA) by 31% (n=4; p<0.05 vs. control) and catecholamine release from NGF-treated PC12 cells by 229% (n=3-5; p<0.001), indicating a DHEA-S-induced shift towards neuroendocrine differentiation. On a molecular level, DHEA-S diminished NGF-induced ERK1/2 phosphorylation. Taken together, DHEA-S inhibited NGF-induced proliferation and neuronal differentiation and shifted cells towards a more endocrine phenotype. Interference of DHEA-S with NGF-stimulated ERK1/2 activation might be involved in this effect. Our study provides support for the notion that adrenocortical-derived DHEA-S impacts adrenomedullary chromaffin cells during development and differentiation.
authors.affiliation: Carl Gustav Carus University Hospital, Medical Clinic III, University of Dresden, Germany. krugaw@mail.nih.gov
authors.forename: Alexander W
authors.initials: AW
authors.lastname: Krug
authors.forename: Heike
authors.initials: H
authors.lastname: Langbein
authors.forename: Christian G
authors.initials: CG
authors.lastname: Ziegler
authors.forename: Stefan R
authors.initials: SR
authors.lastname: Bornstein
authors.forename: Graeme
authors.initials: G
authors.lastname: Eisenhofer
authors.forename: Monika
authors.initials: M
authors.lastname: Ehrhart-Bornstein
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects*; D053379:Chromogranin A / Q000378:metabolism; D019314:Dehydroepiandrosterone Sulfate / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D020932:Nerve Growth Factor / Q000378:metabolism / Q000494:pharmacology; D016716:PC12 Cells / Q000187:drug effects / Q000502:physiology; D051381:Rats; D050825:Synaptosomal-Associated Protein 25 / Q000378:metabolism
chemical_list: D053379:Chromogranin A; D050825:Synaptosomal-Associated Protein 25; D019314:Dehydroepiandrosterone Sulfate; D020932:Nerve Growth Factor; D048049:Extracellular Signal-Regulated MAP Kinases; D004298:Dopamine