Guanosine triphosphate-sensitive adenylate cyclase of adrenocorticotrophic hormone- and prostaglandin-resistant human adrenocortical tumors.

The guanosine triphosphate (GTP)-sensitive adenylate cyclase was studied In the crude membranes of three adrenocorticotrophlc hormone (ACTH)-resistant tumors and one prostaglandln E, (PGEi)-reslstant human adrenocortical tumor. In the ACTH-reslstant tumors, the steroidogenesis of Isolated adrenocortical cells was not stimu lated by ACTH,_24but was enhanced by PGE,; whereas in the PGErlnsensltive tumor, PGE, had no effect but ACTH stimulated steroldogenesis. The cortisol production of cells from all four tumors was stimulated by N6,O2-dibutyryl cyclic adenosine 3 :5 -monophosphate. Binding stud ies with labeled ACTH,_24,ACTH,, ,„ and PGE, revealed that the hormone resistance was associated with a selec tive alteration of the ACTH or the PGE, receptor. The adenylate cyclase activity of ACTH-resistant tumor mem branes was not stimulated by ACTH but was normally stimulated by PGE,. Conversely, in the PGE,-insensitive tumor, the enzyme activity was not enhanced by PGE, but was normally increased by ACTH, j,. 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 -guanylylmethylenediphosphonate 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 PGE, receptor of the ACTHresistant tumors and the ACTH receptor of the PGE,resistant tumor). Our results are thus consistent with the fact that, in human adrenocortical tumors, the ACTH and PGE, receptors can be independently affected, the ade nylate 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.