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Chemokine Stromal Cell-Derived Factor 1 Induces Proliferation and Growth Hormone Release in GH4C1 Rat Pituitary Adenoma Cell Line through Multiple Intracellular Signals

Section of Pharmacology, Department of Oncology Biology and Genetics (T.F., F.D., A.B., C.P., S.T., S.A., A.P., A.C., G.S.), Unit INFM, Department of Physics, (S.C., M.R.), and Division of Neurosurgery, Department of Neuroscience, Ophthalmology, and Genetics (G.Z., R.S.), University of Genova, Genova, Italy

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, SDF1 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: SDF1 increased cytosolic [Ca²⁺] and activated Pyk2, extracellular signal-regulated kinases 1 and 2 (ERK1/2), and large-conductance Ca²⁺-activated K⁺ channels (BK_Ca) 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 SDF1-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 SDF1-dependent activation of ERK1/2, Pyk2, and BK_Ca channels. From these experiments, we observed that the inhibition of [Ca²⁺]_i increase or BK_Ca channel activity did not affect ERK1/2 activation by SDF1; Pyk2 activation was purely Ca²⁺-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 SDF1-dependent increase of [Ca²⁺]_i activates Pyk2, which in turn regulates BK_Ca channel activity. Conversely, ERK1/2 activation is an independent phenomenon. In conclusion, we demonstrate that SDF1 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.

Address correspondence to: Dr. Tullio Florio, Sezione Farmacologia, Dipartimento Oncologia, Biologia e Genetica, Università di Genova, Largo Rosanna Benzi 10, 16132 Genova, Italy. E-mail: tullio.florio{at}unige.it

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