title: 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.affiliation: Section of Pharmacology, Department of Oncology Biology and Genetics, University of Genova, Italy. tullio.florio@unige.it
authors.forename: Tullio
authors.initials: T
authors.lastname: Florio
authors.forename: Silvia
authors.initials: S
authors.lastname: Casagrande
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Diana
authors.forename: Adriana
authors.initials: A
authors.lastname: Bajetto
authors.forename: Carola
authors.initials: C
authors.lastname: Porcile
authors.forename: Gianluigi
authors.initials: G
authors.lastname: Zona
authors.forename: Stefano
authors.initials: S
authors.lastname: Thellung
authors.forename: Sara
authors.initials: S
authors.lastname: Arena
authors.forename: Alessandra
authors.initials: A
authors.lastname: Pattarozzi
authors.forename: Alessandro
authors.initials: A
authors.lastname: Corsaro
authors.forename: Renato
authors.initials: R
authors.lastname: Spaziante
authors.forename: Mauro
authors.initials: M
authors.lastname: Robello
authors.forename: Gennaro
authors.initials: G
authors.lastname: Schettini
mesh_terms: D000236:Adenoma / Q000378:metabolism*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D013006:Growth Hormone / Q000378:metabolism*; D010902:Pituitary Gland / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D010911:Pituitary Neoplasms / Q000378:metabolism*; D051381:Rats; D019718:Receptors, CXCR4 / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D054377:Chemokine CXCL12; D019743:Chemokines, CXC; C486264:Cxcr4 protein, rat; D019718:Receptors, CXCR4; D013006:Growth Hormone; D002118:Calcium