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 language | English |
|---|---|
| Pages (from-to) | 539-546 |
| Number of pages | 8 |
| Journal | Molecular Pharmacology |
| Volume | 69 |
| Issue number | 2 |
| DOIs | |
| Publication status | Published - 2006 |
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ASJC Scopus subject areas
- Pharmacology
Cite this
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 journal › Article
}
TY - JOUR
T1 - Chemokine stromal cell-derived factor 1α induces proliferation and growth hormone release in GH4C1 rat pituitary adenoma cell line through multiple intracellular signals
AU - Florio, Tullio
AU - Casagrande, Silvia
AU - Diana, Fabrizio
AU - Bajetto, Adriana
AU - Porcile, Carola
AU - Zona, Gianluigi
AU - Thellung, Stefano
AU - Arena, Sara
AU - Pattarozzi, Alessandra
AU - Corsaro, Alessandro
AU - Spaziante, Renato
AU - Robello, Mauro
AU - Schettini, Gennaro
PY - 2006
Y1 - 2006
N2 - 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.
AB - 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.
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U2 - 10.1124/mol.105.015255
DO - 10.1124/mol.105.015255
M3 - Article
VL - 69
SP - 539
EP - 546
JO - Molecular Pharmacology
JF - Molecular Pharmacology
SN - 0026-895X
IS - 2
ER -