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Stimulation of Cell Proliferation and Inhibition of Differentiation Expression by Tumor-promoting Phorbol Esters in Dog Thyroid Cells in Primary Culture¹

Institute of Interdisciplinary Research (IRIBHN), School of Medicine, Free University of Brussels, Campus Erasme, Route de Lennik 808, B-1070 Brussels, and Biology Department, Euratom, Brussels, Belgium

12-O-Tetradecanoylphorbol-13-acetate (TPA) and 4ß-phorbol 12,13-dibutyrate (PDBU) are potent tumor promoters and share several biological activities of epidermal growth factor (EGF). We have shown previously that EGF stimulates DNA synthesis and proliferation and inhibits TSH-induced markers of differentiation in dog thyroid follicle-derived primary cultures. Using this system, we have examined the biological action of TPA and PDBU in reference to that of EGF.

Low concentrations (1.6–16 nM) and to a lesser extent higher concentrations (>1.6 µM) of TPA and PDBU stimulated cell proliferation in a 1% serum, hormone-supplemented medium and triggered the DNA synthesis revealed by autoradiography in cells which were quiescent before stimulation in serum-free conditions. EGF, TSH, and dibutyryl cyclic adenosine 3':5'-monophosphate separately also induce DNA synthesis, but they produce little if any effects additive to those of TPA. In fact, TPA appeared to inhibit the mitogenic effects of EGF. Moreover like EGF, phorbol esters strongly inhibited in 2 days the morphological effects of TSH and basal and TSH-stimulated iodide transport capacity and thyroglobulin messenger RNA accumulation, two markers of thyroid differentiation. TPA also inhibited the expression of differentiation stimulated by dibutyryl cyclic adenosine 3':5'-monophosphate indicating a post-cyclic adenosine 3':5'-monophosphate site of action. TPA and EGF shared long-term morphological effects such as the induction of an elongated fusiform shape, but not acute effects. The thyroid cells progressively and spontaneously escaped both the mitogenic and differentiation-inhibiting effects of TPA and PDBU, while, as shown previously, these parameters are stably modified by continuous culture with EGF. This suggests specific desensitization processes to phorbol esters.

As evidence is accumulating that phorbol esters act at least partly by stimulating the calcium-activated, phospholipid-dependent protein kinase C, our results shed light on the possible key role of this kinase in carcinogenesis and in the normal control of proliferation and expression of differentiation in the thyroid gland. Additionally they suggest that complex interactions occur between the mechanisms of action of EGF and of phorbol esters in the thyroid cell.

¹ The text has been elaborated in part within the framework of the Belgian Programme for the reinforcement of the scientific potential in the new technologies, PREST (Prime Minister's Office for Science Policy). The scientific responsibility for the text is assumed by its authors. This work was also done within the framework of Euratom Contract Bio-C-360-81-B, and partially thanks to grants from the Action Concertée du Ministère de la Politique Scientifique, the Cancer Research Funds of the Caisse Générale d'Epargne et de Retraite and the Loterie Nationale. S. R. is a Research Fellow of the Institut pour l'Encouragement de la Recherche Scientifique dans l'Industrie et l'Agriculture (IRSIA).

² To whom requests for reprints should be addressed, at the Institute of the Interdisciplinary Research, Campus Erasme, Route de Lennik, 808, B-1070 Brussels, Belgium.

Received 3/15/85. Revised 10/ 4/85. Accepted 10/ 8/85.

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