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Pharmacology, Molecular Identification and Functional Characteristics of Vasoactive Intestinal Peptide Receptors in Human Breast Cancer Cells¹

INSERM U. 55, Unité de recherches sur les neuropeptides digestifs et le diabète, Hôpital Saint-Antoine, 184 rue du Faubourg Saint-Antoine, 75571 Paris Cedex 12, [C. G., W. B.]; and Laboratoire de pharmacologie cellulaire, Université de Paris VII, et INSERM U. 204, Cinétique des populations cellulaires en hématologie et en cancérologie, 2 place du Dr. Fournier Hôpital Saint-Louis, 75475 Paris Cedex 10 [P. d. C., F. C.], France

High-performance liquid chromatography-purified ¹²⁵I-vasoactive intestinal peptide (VIP) bound to T-47D human breast cancer cells in a specific, saturable, and reversible manner. Scatchard plots were compatible with the presence of one class of VIP receptors with high affinity (K_d = 4.5 x 10^-10 M VIP, and B_max = 293 fmol/mg protein). The neuropeptide and its natural analogues inhibited the binding of ¹²⁵I-VIP and stimulated cyclic AMP (cAMP) generation in T-47D cells 96-fold (EC₅₀ = 7 x 10^-10 M VIP), in the following order or potency: VIP > helodermin > human peptide with N-terminal histidine and C-terminal methionine > human pancreatic growth hormone-releasing factor > human secretin. In contrast, ¹²⁵I-VIP binding was not displaced by pancreatic glucagon, human oxyntomodulin, truncated glucagon-like peptide-1, glucagon-like peptide-2, the somatostatin analogue SMS 201–995, gastric inhibitory peptide, and a series of steroid hormones or peptides unrelated to VIP. VIP also increased cAMP generation in seven other human breast cancer cell lines: H4-66B, HSL 53, HSL 78, MCF 7, MDA-MB231, T-47D2, and ZR75-1. Adenylate cyclase activity rose from 72.2 ± 14 to 1069 ± 66 pmol cAMP/min mg protein after the addition of 10^-7 M VIP to T-47D plasma membranes. In agreement with our pharmacological results and the Scatchard analysis of the binding data, sodium dodecyl sulfate-polyacrylamide gel electrophoresis of the solubilized receptor in the T-47D membranes permitted identification of one autoradiographic band with a molecular weight of 69,000. The sensitivity of the M_r 69,000 binding site to GTP and low doses of VIP implies that in T-47D cells, this component constitutes the membrane domain involved in the functional regulation of adenylate cyclase by VIP receptors. Our results indicate a role for the VIP receptor-cAMP system in human breast cancer cells.

¹ Supported in part by a research Grant CIDIL No. 1150/86 to C. G.

² To whom requests for reprints should be addressed.

Received 12/ 4/87. Revised 5/11/88. Accepted 6/ 9/88.

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