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Modulation of Peptide Binding to Specific Receptors on Rat Pituitary Cells by Tumor-promoting Phorbol Esters: Decreased Binding of Thyrotropin-releasing Hormone and Somatostatin as Well as Epidermal Growth Factor¹

Laboratory of Toxicology, Harvard School of Public Health, and the Department of Pharmacology, Harvard Medical School, Boston, Massachusetts 02115

Phorbol esters increase prolactin synthesis and release and inhibit growth hormone production by GH₄C₁ cells, a clonal strain of rat pituitary cells. We examined the actions of phorbol esters on the binding of peptides that regulate the function of GH₄C₁ cells and found that phorbol esters decreased the specific binding of epidermal growth factor (EGF), thyrotropinreleasing hormone (TRH), and somatostatin. 12-O-Tetradecanoyl-13-phorbol acetate (TPA) at 100 ng/ml decreased ¹²⁵I-EGF binding to 15% of control within 1 hr, ³H-TRH binding to 30% of control after 4 hr, and ¹²⁵I-Tyr¹-somatostatin binding to 40% of control after 24 hr. The action of TPA on ¹²⁵I-EGF and ³H-TRH binding was temperature dependent, occurring at 37° but not at 4°, and was reversed within 72 hr after removal of TPA. By Scatchard analysis of ¹²⁵I-EGF-binding data, TPA (100 ng/ml) decreased the concentration dependence of ¹²⁵I-EGF binding (7- to 10-fold) when binding was assayed at 37° and decreased both the apparent affinity (2- to 6-fold) and the number of ¹²⁵I-EGF-binding sites (by 25 to 50%) when binding was assayed at 4°. The decrease in ³H-TRH binding induced by TPA (100 ng/ml) was due to a 2- to 5-fold decrease in the apparent affinity of binding at 37°. Thus, unlike findings reported for certain other cell lines, phorbol esters induce an alteration in membrane function in GH₄C₁ cells which decreases the binding to specific receptors for more than one regulatory peptide. Modulation of receptors for regulatory ligands may play a role in the mechanism by which phorbol esters promote neoplastic transformation, but the action on "growth factor" receptors cannot be considered specific in all cell types.

¹ This investigation was supported in part by Research Grant AM 11011 from the National Institute of Arthritis, Diabetes, Kidney and Digestive Diseases, Center Grant ES 00002, and Cooperative Agreement CR 807809 with the Environmental Protection Agency.

² To whom requests for reprints should be addressed, at Laboratory of Toxicology, Harvard School of Public Health, 665 Huntington Ave., Boston, Mass. 02115.

Received 3/29/82. Accepted 7/18/82.

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