Chemokine stromal cell-derived factor 1α induces proliferation and growth hormone release in GH4C1 rat pituitary adenoma cell line through multiple intracellular signals

Tullio Florio, Silvia Casagrande, Fabrizio Diana, Adriana Bajetto, Carola Porcile, Gianluigi Zona, Stefano Thellung, Sara Arena, Alessandra Pattarozzi, Alessandro Corsaro, Renato Spaziante, Mauro Robello, Gennaro Schettini

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Abstract

We used GH4C1 cells as a model to study the effects of the chemokine stromal cell-derived factor 1 (SDF1) in pituitary functions. In these cells, SDF1α induced proliferation and growth hormone secretion, suggesting a possible regulatory role for this chemokine at pituitary level. We evaluated the intracellular signaling involved in these effects: SDF1α increased cytosolic [Ca2+] and activated Pyk2, extracellular signal-regulated kinases 1 and 2 (ERK1/2), and large-conductance Ca2+-activated K + channels (BKCa) channels. To correlate these intracellular effectors with the proliferative and secretory effects, we inhibited their activity using BAPTA-AM (Ca2+ chelator), 2′-amino-3′-methoxyflavone (PD98059; a mitogen-activated protein kinase kinase inhibitor), salicylate (Pyk2 inhibitor), and tetraethyl ammonium (K+ channel blocker). All of these compounds reverted SDF1α-induced proliferation, suggesting the involvement of multiple intracellular pathways. Conversely, only BAPTA-AM reverted growth hormone secretion. To identify a possible cross-talk and a molecular ordering among these pathways, we tested these antagonists on SDF1α-dependent activation of ERK1/2, Pyk2, and BKCa channels. From these experiments, we observed that the inhibition of [Ca2+]i increase or BKCa channel activity did not affect ERK1/2 activation by SDF1α; Pyk2 activation was purely Ca2+-dependent, not involving ERK1/2 or BKCa channels; and BKCa channel activity was antagonized by Pyk2 but not by ERK1/2 inhibitors. These data suggest that an SDF1α-dependent increase of [Ca2+]i activates Pyk2, which in turn regulates BKCa channel activity. Conversely, ERK1/2 activation is an independent phenomenon. In conclusion, we demonstrate that SDF1α causes both proliferation and growth hormone release from pituitary adenoma cells, suggesting that the activation of CXCR4 may represent a novel regulatory mechanism for growth hormone secretion and pituitary cell proliferation, which may contribute to pituitary adenoma development.

Original languageEnglish
Pages (from-to)539-546
Number of pages8
JournalMolecular Pharmacology
Volume69
Issue number2
DOIs
Publication statusPublished - 2006

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Chemokine CXCL12
Pituitary Neoplasms
Chemokines
Growth Hormone
Mitogen-Activated Protein Kinase 3
Mitogen-Activated Protein Kinase 1
Cell Line
Calcium-Activated Potassium Channels
Salicylates
Mitogen-Activated Protein Kinase Kinases
Chelating Agents
Ammonium Compounds
Cell Proliferation

ASJC Scopus subject areas

  • Pharmacology

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Chemokine stromal cell-derived factor 1α induces proliferation and growth hormone release in GH4C1 rat pituitary adenoma cell line through multiple intracellular signals. / Florio, Tullio; Casagrande, Silvia; Diana, Fabrizio; Bajetto, Adriana; Porcile, Carola; Zona, Gianluigi; Thellung, Stefano; Arena, Sara; Pattarozzi, Alessandra; Corsaro, Alessandro; Spaziante, Renato; Robello, Mauro; Schettini, Gennaro.

In: Molecular Pharmacology, Vol. 69, No. 2, 2006, p. 539-546.

Research output: Contribution to journalArticle

Florio, T, Casagrande, S, Diana, F, Bajetto, A, Porcile, C, Zona, G, Thellung, S, Arena, S, Pattarozzi, A, Corsaro, A, Spaziante, R, Robello, M & Schettini, G 2006, 'Chemokine stromal cell-derived factor 1α induces proliferation and growth hormone release in GH4C1 rat pituitary adenoma cell line through multiple intracellular signals', Molecular Pharmacology, vol. 69, no. 2, pp. 539-546. https://doi.org/10.1124/mol.105.015255
Florio, Tullio ; Casagrande, Silvia ; Diana, Fabrizio ; Bajetto, Adriana ; Porcile, Carola ; Zona, Gianluigi ; Thellung, Stefano ; Arena, Sara ; Pattarozzi, Alessandra ; Corsaro, Alessandro ; Spaziante, Renato ; Robello, Mauro ; Schettini, Gennaro. / Chemokine stromal cell-derived factor 1α induces proliferation and growth hormone release in GH4C1 rat pituitary adenoma cell line through multiple intracellular signals. In: Molecular Pharmacology. 2006 ; Vol. 69, No. 2. pp. 539-546.
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AU - Diana, Fabrizio

AU - Bajetto, Adriana

AU - Porcile, Carola

AU - Zona, Gianluigi

AU - Thellung, Stefano

AU - Arena, Sara

AU - Pattarozzi, Alessandra

AU - Corsaro, Alessandro

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