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Galanin Stimulates Ca²⁺ Mobilization, Inositol Phosphate Accumulation, and Clonal Growth in Small Cell Lung Cancer Cells

Imperial Cancer Research Fund, P. O. Box 123, Lincoln's Inn Fields, London WC2A 3PX, United Kingdom

Addition of the neuropeptide galanin to small cell lung cancer (SCLC) cells loaded with the fluorescent Ca²⁺ indicator fura-2-tetraacetoxyme-thylester causes a rapid and transient increase in the intracellular concentration of Ca²⁺ ([Ca²⁺]_i) followed by homologous desensitization. Galanin increased [Ca²⁺]_i in a concentration-dependent fashion with half-maximum effect (EC₅₀) at 20–22 nM in H69 and H510 SCLC cells. Galanin mobilized Ca²⁺ from intracellular stores since its effects on [Ca²⁺]_i were not blocked by chelation of extracellular Ca²⁺. Pretreatment with pertussis toxin (200 ng/ml for 4 h) did not prevent galanin-induced Ca²⁺ mobilization. In contrast, direct activation of protein kinase C with phorbol esters attenuated the Ca²⁺ response induced by galanin. The effects of galanin could be dissociated from changes in membrane potential: galanin did not increase membrane potential in SCLC cells loaded with bis(1,3-diethyltiobarbiturate)-trimethineoxonol and induced Ca²⁺ mobilization in depolarized SCLC cells, i.e., in cells suspended in a solution containing 145 mM K⁺ instead of Na⁺. Galanin also caused an increase in the formation of inositol phosphates in a time- and dose-dependent manner (EC₅₀ 10 nM). A rapid increase in the inositol tris-phosphate fraction was followed by a slower increase in the inositol monophosphate fraction. Galanin stimulated clonal growth of both H69 and H510 cells in semisolid (agarose-containing) medium. This growth-promoting effect was sharply dependent on galanin concentration (EC₅₀ 20 nM) and markedly inhibited by [Arg⁶,D-Trp^7,9,MePhe⁸]substance P, a recently identified broad spectrum neuropeptide antagonist. The results show for the first time that galanin receptors are coupled to inositol phosphate and [Ca²⁺]_i responses in SCLC cells and, in particular, that this neuropeptide can act as a direct growth factor for these human cancer cells.

¹ To whom requests for reprints should be addressed.

Received 8/24/90. Accepted 1/ 9/91.

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