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

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, SDF1alpha 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: SDF1alpha increased cytosolic [Ca(2+)] and activated Pyk2, extracellular signal-regulated kinases 1 and 2 (ERK1/2), and large-conductance Ca(2+)-activated K(+) channels (BK(Ca)) channels. To correlate these intracellular effectors with the proliferative and secretory effects, we inhibited their activity using BAPTA-AM (Ca(2+) 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 SDF1alpha-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 SDF1alpha-dependent activation of ERK1/2, Pyk2, and BK(Ca) channels. From these experiments, we observed that the inhibition of [Ca(2+)](i) increase or BK(Ca) channel activity did not affect ERK1/2 activation by SDF1alpha; Pyk2 activation was purely Ca(2+)-dependent, not involving ERK1/2 or BK(Ca) channels; and BK(Ca) channel activity was antagonized by Pyk2 but not by ERK1/2 inhibitors. These data suggest that an SDF1alpha-dependent increase of [Ca(2+)](i) activates Pyk2, which in turn regulates BK(Ca) channel activity. Conversely, ERK1/2 activation is an independent phenomenon. In conclusion, we demonstrate that SDF1alpha 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.

• Authors: 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
• Journal: Molecular pharmacology (Mol Pharmacol) Vol. 69 Issue 2 Pg. 539-46 (Feb 2006) ISSN: 0026-895X [Print] United States
• PMID: 16258074 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Chemokine CXCL12
• Chemokines, CXC
• Cxcr4 protein, rat
• Receptors, CXCR4
• Growth Hormone
• Calcium

Topics

• Adenoma (metabolism)
• Animals
• Calcium (metabolism)
• Calcium Signaling (drug effects)
• Cell Line, Tumor
• Cell Proliferation
• Chemokine CXCL12
• Chemokines, CXC (genetics, metabolism, pharmacology)
• Growth Hormone (metabolism)
• Pituitary Gland (drug effects, metabolism, physiology)
• Pituitary Neoplasms (metabolism)
• Rats
• Receptors, CXCR4 (agonists, genetics, metabolism)
• Signal Transduction (drug effects)