Tumor-Promoting Phorbol Esters Affect Production of Prolactin and Growth Hormone by Rat Pituitary Cells*

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Abstract
GH4C1, cells are a strain of rat pituitary cells which synthesize and secrete both PRL and GH. Phorbol esters, which are potent tumor promoters in mouse skin and have diverse actions in a variety of cell and tissue systems, were found to alter hormone production by GH4C1 cells. 12-o-Tetradecanoylphorbol- 13-acetate (TPA), the most potent phorbol ester, stimulated both PRL synthesis and release. The synthesis of PRL was stimulated 2.3- to 6.2-fold over control values after 3 days of treatment; the ED50 for TPA was 8.9 + 2.1 nM (5.5 + 1.3 ng/ml). The release of stored PRL was stimulated within 10 min of the addition of 100 ng/ml TPA to the culture medium. Maximum stimulation of release was 1.3- to 2.3-fold over control, and the ED50 for TPA was 13.2 + 2.3 nM (8.1 + 1.4 ng/ml). Another tumor-promoting phorbol ester, phorbol 12,13-didecanoate (PDD), stimulated PRL synthesis and release to the same maximum extent at TPA, but two biologically inactive compounds, 4α-PDD and phorbol, had no effect. The stimulation of PRL release by TPA was a Ca++-dependent process; Co++, a competitive antagonist of Ca++, at 2.0 mM blocked completely the stimulation of PRL release by 100 ng/ml TPA, and this block was overcome by 2.0 mM Ca++, but not by 2.0 mM Mg++. Although phorbol esters stimulate prostaglandin (PG) synthesis in certain other cell types, PGs were not required for TPA action in GH4C1 cells. Indomethacin, a PG cyclooxygenase inhibitor, at 200 ng/ml did not inhibit the stimulation of PRL synthesis and release by TPA. Furthermore, there was no detectable (2 or PGF2α in the medium of control or TPA-treated cells. In GH3 cells, a related cell strain, TPA (100 ng/ml) decreased GH production in both control and hydrocortisone-stimulated cells to 35% of untreated control values after 3 days of incubation. TPA also altered cell morphology, but had little or no effect on cell growth1. We conclude that GH cells provide a useful system to study the mechanisms of phorbol ester action on differentiated functions.

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