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Guanosine Triphosphate-sensitive Adenylate Cyclase of Adrenocorticotrophic Hormone- and Prostaglandin-resistant Human Adrenocortical Tumors¹

Unité de Recherches sur le Contróle Hormonal des Activités Celluiaires, INSERM, U. 162, Hópital Debrousse, 29 Rue Soeur Bouvier, 69322 Lyon Cedex 1, France

The guanosine triphosphate (GTP)-sensitive adenylate cyclase was studied in the crude membranes of three adrenocorticotrophic hormone (ACTH)-resistant tumors and one prostaglandin E₁ (PGE₁)-resistant human adrenocortical tumor. In the ACTH-resistant tumors, the steroidogenesis of isolated adrenocortical cells was not stimulated by ACTH_1–24 but was enhanced by PGE₁; whereas in the PGE₁-insensitive tumor, PGE₁ had no effect but ACTH stimulated steroidogenesis. The cortisol production of cells from all four tumors was stimulated by N⁶,O²-dibutyryl cyclic adenosine 3':5'-monophosphate. Binding studles with labeled ACTH_1–24, ACTH_11–24, and PGE₁ reveaied that the hormone resistance was assoclated with a selective alteration of the ACTH or the PGE₁ receptor. The adenylate cyclase activity of ACTH-resistant tumor membranes was not stimulated by ACTH but was normally stimulated by PGE₁. Conversely, in the PGE₁-insensitive tumor, the enzyme activity was not enhanced by PGE₁ but was normally increased by ACTH_1–24. In all four tumors, the adenylate cyclase activity was normal regarding basal levels and NaF stimulation. In addition 5'-guanylylimidodiphosphate and, to a lesser extent, GTP and 5'-guanylyl-methylenediphosphonate were effective in stimulating the basal adenylate cyclase activity of the four tumors and in enhancing the hormone effect on the intact hormone receptor complex (i.e., the PGE₁ receptor of the ACTH-resistant tumors and the ACTH receptor of the PGE₁-resistant tumor). Our results are thus consistent with the fact that, in human adrenocortical tumors, the ACTH and PGE₁ receptors can be independently affected, the adenylate cyclase catalytic subunit and the GTP-sensitive subunit being unaltered by this selective tumoral process. This suggests that the GTP-sensitive subunit may be more closely related to the catalytic subunit of the enzyme than to the hormone-binding site.

¹ This work was supported by grants from Institut National de la Santé et de la Recherche Médicale (ATP No. 24.75.47 and 76.5.473), the Ligue Nationale Française contre le Cancer, and the Fondation pour la Recherche Médicale Française.

² Present address: Centre de Recherche Merrell International, 16 Rue d'Ankara, 67000 Strasbourg, France.

³ To whom requests for reprints should be addressed.

Received 10/17/77. Accepted 1/11/78.