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Effect of Guanine and Adenine Nucleotides on Bombesin-stimulated Phospholipase C Activity in Membranes from Swiss 3T3 and Small Cell Lung Carcinoma Cells¹

NCI-Navy Medical Oncology Branch, National Cancer Institute, NIH, Bethesda, Maryland 20814 [Y. S., J. V., J. B. T., E. A. S.]; Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Isael [Y. S.]; and Department of Medicine, Division of Medical Oncology, Vincent T. Lombardi Cancer Research Center, Georgetown University School of Medicine, Washington, DC 20007 [E. A. S.]

In [³H]inositol-labeled membranes prepared from Swiss mouse 3T3 and human small cell lung carcinoma cells, [Tyr⁴]-bombesin stimulated production of water-soluble inositol phosphates. The reaction was stimulated by guanosine 5'-O-[3-thiotriphosphate] and was specifically inhibited by both [Leu¹³--CH₂NHLeu¹⁴]-bombesin and the antibombesin antibody 2A11. [Tyr⁴]-bombesin-induced activation of phospholipase C is most apparent in Ca²⁺-depleted conditions (<1 µM [Ca²⁺]_free). The kinetics of activation by ligand also demonstrate that [Tyr⁴]-bombesin-dependent phospholipase C activation is most apparent at [Mg²⁺]_free of 0.2 µM. At millimolar concentrations of [Mg²⁺]_free, there is considerably less dependence on [Tyr⁴]-bombesin for activation of phospholipase C. ATP is not necessary for initial activation of phospholipase C, and ß,-imidoadenosine-5'-triphosphate does not inhibit the reaction. These results demonstrate that in these cell types [Tyr⁴]-bombesin activates phospholipase C in conjunction with guanine nucleotides. Phospholipase C-coupled guanine nucleotide regulatory proteins would be appropriately considered as novel targets for the development of therapeutic strategies in small cell lung carcinoma.

¹ Supported in part by Biomedical Research Support Grant RR 5360 to Georgetown University School of Medicine from the NIH.

² To whom requests for reprints should be addressed, at Medicine Branch, National Cancer Institute, National Institutes of Health, Bldg. 10., Room 12N228, 9000 Rockville Pike, Bethesda, MD 20892.

Received 3/ 1/90. Revised 5/24/90.