Evidence for Decreased Activity of Guanine Nucleotide Binding Protein in Adenylate Cyclase of Cell Membranes in Human ACTH-Unresponsive Adrenocortical Carcinoma

抄録

The present investigation was performed in order to study the properties of abnormal membrane function related to ACTH receptor-adenylate cyclase system interaction in human ACTH-unresponsive adrenocortical cancer. Two tissues of adrenocortical cancer obtained from a patient with Cushing's syndrome (CS) and a case presenting no abnormal endocrinological findings (NF) were used for in vitro studies, comparing with three normal adrenal tissues. The addition of ACTH alone and ACTH plus 10^-6 M GppNHp did not enhance the adenylate cyclase (AC) activity in the CS and NF tissues. Relative insensitivity of AC to GTP, GppNHp, and cholera toxin was observed for the NF tissue, while the rate of response to GppNHp for the CS tissue which also showed relative insensitivity to GTP and cholera toxin was similar to that for the normal tissues. Forskolin which is reported to directly activate the catalytic unit of the AC complex increased the AC activity of both CS and NF tissues as well as that of the normal tissues. Therefore, the function of the catalytic unit itself may be rather well preserved in these tumor tissues. These results suggest that the lack of ACTH receptor at the cell membrane surface might be responsible for ACTH-unresponsiveness in the CS tissue, although an accelerated degradation of GTP could contribute to decreased activity of GTP-binding protein. On the other hand, it might be speculated from the present observation that post-receptor interaction of AC complex for activation of AC, especially due to insensitivity of guanine nucleotide-binding protein for guanine nucleotide and cholera toxin, may be impaired in the NF tissue and this might lead to decreased AC activity in response to ACTH in the NF tissue.