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. 1975 Sep;56(3):536–547. doi: 10.1172/JCI108122

ACTH and prostaglandin receptors in human adrenocortical tumors. Apparent modification of a specific component of the ACTH-binding site.

J M Saez, A Dazord, D Gallet
PMCID: PMC301900  PMID: 169292

Abstract

The failure of certain adrenal tumors to respond to ACTH was investigated in vivo be administration of corticotropin-(1-24)-tetracosapeptide (ACTH1-24) and dexamethasone and in vitro by studying the binding properties of ACTH1-24 and prostaglandin E1 (PGE1) and their effect on adenylate cyclase activity of the tumors' crude membranes; in addition, in five cases the stimulation of cortisol production in isolated adrenal cells by both hormones and dibuttyryl cyclic adenosine 3',5'-monophosphate (cAMP) was also studied. The results obtained in 13 hormone-producing tumors of the human adrenal cortex, i.e. 10 carcinomas and 3 adenomas, were compared with those found in normal human adrenal glands. According to the adenylate cyclase responses to ACTH1-24 and PGE1, the tumors fall into different categories. In the first group are six rumors in which the adenylate cyclase was stimulated by both ACTH1-24 and PGE; in addition specific binding could be demonstrated for the two hormones in all six. The binding affinity for 125I-ACTH1-24 was found to be about 10 times higher than that for 125I-ACTH11-24. In the one tumor in which the experiment was performed, bound 125I-ACTH1-24 was displaced by ACTH1-10. These results are similar to the ones found in normal human adrenal preparations. For two rumors of the group in which ACTH did not increase steroidogenesis in vivo, the biochemical abnormality might be located beyond cAMP formation. A second group encompasses six tumors in which the steroidogenesis in vivo and the adenylate cyclase activity were insensitive to ACTH1-24 but in which the enzyme was stimulated by PGE1 and NaF. However, these preparations bound 125I-ACTH1-24 and 125I-ACTH11-24, the binding affinity being similar for both peptides but 10 times lower than the one found in normal adrenal cortex for 125I-ACTH1-24. In the only case of this group where it was tested, ACTH1-10 did not displace bound 125I-ACTH1-24. This result strongly suggests the possibility of a modification or a loss of the receptor site that binds the N-terminal sequency (1-10) of ACTH, the biologically active part of the molecule. In the last tumor, both PGE1 and ACTH were unable to stimulate adenylate cyclase activity and steroid production in a preparation of isolated adrenal cells, although steroidogenesis was stimulated by dibutyryl though steroidogenesis was stimulated by dibutyryl cAMP. No specific binding for PGE1 could be demonstrated. However, 125I-ACTH1-24 and 125I-ACTH11-24 were found to be bound to the tumor with the same affinity.

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Selected References

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  1. Dazord A., Gallet D., Bertrand J., Saez J. M. Action du calcium, de l'EGTA et de l'EDTA sur l'activité adényl-cyclasique de préparations subcellulaires de corticosurrénales. C R Acad Sci Hebd Seances Acad Sci D. 1973 Nov 5;277(18):1917–1920. [PubMed] [Google Scholar]
  2. Dazord A., Morera A. M., Bertrand J., Saez J. M. Prostaglandin receptors in human and ovine adrenal glands: binding and stimulation of adenyl cyclase in subcellular preparations. Endocrinology. 1974 Aug;95(2):352–359. doi: 10.1210/endo-95-2-352. [DOI] [PubMed] [Google Scholar]
  3. FEW J. D. A method for the analysis of urinary 17-hydroxycorticosteroids. J Endocrinol. 1961 Mar;22:31–46. doi: 10.1677/joe.0.0220031. [DOI] [PubMed] [Google Scholar]
  4. Finn F. M., Widnell C. C., Hofmann K. Localization of an adrenocorticotropic hormone receptor on bovine adrenal cortical membranes. J Biol Chem. 1972 Sep 25;247(18):5695–5702. [PubMed] [Google Scholar]
  5. Forest M. G., Sizonenko P. C., Cathiard A. M., Bertrand J. Hypophyso-gonadal function in humans during the first year of life. 1. Evidence for testicular activity in early infancy. J Clin Invest. 1974 Mar;53(3):819–828. doi: 10.1172/JCI107621. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. GLENN E. M., NELSON D. H. Chemical method for the determination of 17-hydroxycorticosteroids and 17-ketosteroids in urine following hydrolysis with beta-glucuronidase. J Clin Endocrinol Metab. 1953 Aug;13(8):911–921. doi: 10.1210/jcem-13-8-911. [DOI] [PubMed] [Google Scholar]
  7. Geiger R., Schröder H. G. Synthetische Analoga des Corticotropins. Der Beitrag von Lysin in Position 11 zur biologischen Wirkung. Hoppe Seylers Z Physiol Chem. 1973 Feb;354(2):156–162. [PubMed] [Google Scholar]
  8. Gill G. N. Mechanism of ACTH action. Metabolism. 1972 Jun;21(6):571–588. doi: 10.1016/0026-0495(72)90101-1. [DOI] [PubMed] [Google Scholar]
  9. Grahame-Smith D. G., Butcher R. W., Ney R. L., Sutherland E. W. Adenosine 3',5'-monophosphate as the intracellular mediator of the action of adrenocorticotropic hormone on the adrenal cortex. J Biol Chem. 1967 Dec 10;242(23):5535–5541. [PubMed] [Google Scholar]
  10. HEPPEL L. A., HILMORE R. J. Purification and properties of 5-nucleotidase. J Biol Chem. 1951 Feb;188(2):665–676. [PubMed] [Google Scholar]
  11. Hofmann K., Wingender W., Finn F. M. Correlation of adrenocorticotropic activity of ACTH analogs with degree of binding to an adrenal cortical particulate preparation. Proc Natl Acad Sci U S A. 1970 Oct;67(2):829–836. doi: 10.1073/pnas.67.2.829. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Kitabchi A. E., Sharma R. K. Corticosteroidogenesis in isolated adrenal cells of rats. I. Effect of corticotropins and 3',5'-cyclic nucleotides on corticosterone production. Endocrinology. 1971 May;88(5):1109–1116. doi: 10.1210/endo-88-5-1109. [DOI] [PubMed] [Google Scholar]
  13. LIPSETT M. B., HERTZ R., ROSS G. T. CLINICAL AND PATHOPHYSIOLOGIC ASPECTS OF ADRENOCORTICAL CARCINOMA. Am J Med. 1963 Sep;35:374–383. doi: 10.1016/0002-9343(63)90179-7. [DOI] [PubMed] [Google Scholar]
  14. LOWRY O. H., ROSEBROUGH N. J., FARR A. L., RANDALL R. J. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951 Nov;193(1):265–275. [PubMed] [Google Scholar]
  15. Lefkowitz R. J., Roth J., Pricer W., Pastan I. ACTH receptors in the adrenal: specific binding of ACTH-125I and its relation to adenyl cyclase. Proc Natl Acad Sci U S A. 1970 Mar;65(3):745–752. doi: 10.1073/pnas.65.3.745. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Macchia V., Meldolesi M. F., Chiariello M. Adenyl-cyclase in a transplantable thyroid tumor: loss of ability to respond to TSH. Endocrinology. 1972 Jun;90(6):1483–1491. doi: 10.1210/endo-90-6-1483. [DOI] [PubMed] [Google Scholar]
  17. Murphy B. E. Some studies of the protein-binding of steroids and their application to the routine micro and ultramicro measurement of various steroids in body fluids by competitive protein-binding radioassay. J Clin Endocrinol Metab. 1967 Jul;27(7):973–990. doi: 10.1210/jcem-27-7-973. [DOI] [PubMed] [Google Scholar]
  18. Ney R. L., Hochella N. J., Grahame-Smith D. G., Dexter R. N., Butcher R. W. Abnormal regulation of adenosine 3',5'-monophosphate and corticosterone formation in an adrenocortical carcinoma. J Clin Invest. 1969 Sep;48(9):1733–1739. doi: 10.1172/JCI106139. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Ramachandran J., Choh Hao L. i. Structure-activity relationships of the adrenocorticotropins and melanotropins: the synthetic approach. Adv Enzymol Relat Areas Mol Biol. 1967;29:391–477. doi: 10.1002/9780470122747.ch8. [DOI] [PubMed] [Google Scholar]
  20. Rosenfeld R. S., Hellman L., Roffwarg H., Weitzman E. D., Fukushima D. K., Gallagher T. F. Dehydroisoandrosterone is secreted episodically and synchronously with cortisol by normal man. J Clin Endocrinol Metab. 1971 Jul;33(1):87–92. doi: 10.1210/jcem-33-1-87. [DOI] [PubMed] [Google Scholar]
  21. SNELL K. C., STEWART H. L. Variations in histologic pattern and functional effects of a transplantable adrenal cortical carcinoma in intact, hypophysectomized, and newborn rats. J Natl Cancer Inst. 1959 Jun;22(6):1119–1155. [PubMed] [Google Scholar]
  22. Saez J. M., Bertrand J. Studies on testicular function in children: plasma concentrations of testosterone, dehydroepiandrosterone and its sulfate before and after stimulation with human chorionic gonadotrophin. (1). Steroids. 1968 Dec;12(6):749–761. doi: 10.1016/s0039-128x(68)80029-7. [DOI] [PubMed] [Google Scholar]
  23. Saez J. M., Dazord A., Morera A. M., Bataille P. Interactions of adrenocorticotropic hormone with its adrenal receptors. Degradation of ACTH-1-24 and ACTH-11-24. J Biol Chem. 1975 Mar 10;250(5):1683–1689. [PubMed] [Google Scholar]
  24. Sayers G., Seelig S., Kumar S., Karlaganis G., Schwyzer R., Fujino M. Isolated adrenal cortex cells: ACTH4-23 (NH2), ACTH5-24, ACTH6-24 and ACTH7-23 (NH2); cyclic AMP and corticosterone production. Proc Soc Exp Biol Med. 1974 Jan;145(1):176–181. doi: 10.3181/00379727-145-37772. [DOI] [PubMed] [Google Scholar]
  25. Sayers G., Swallow R. L., Giordano N. D. An improved technique for the preparation of isolated rat adrenal cells: a sensitive, accurate and specfic method for the assay of ACTH. Endocrinology. 1971 Apr;88(4):1063–1068. doi: 10.1210/endo-88-4-1063. [DOI] [PubMed] [Google Scholar]
  26. Schimmer B. P. Adenylate cyclase activity in adrenocorticotropic hormone-sensitive and mutant adrenocortical tumor cell lines. J Biol Chem. 1972 May 25;247(10):3134–3138. [PubMed] [Google Scholar]
  27. Schimmer B. P. Phenotypically variant adrenal tumor cell cultures with biochemical lesions in the ACTH-stimulated steroidogenic pathway. J Cell Physiol. 1969 Oct;74(2):115–122. doi: 10.1002/jcp.1040740203. [DOI] [PubMed] [Google Scholar]
  28. Schorr I., Ney R. L. Abnormal hormone responses of an adrenocortical cancer adenyl cyclase. J Clin Invest. 1971 Jun;50(6):1295–1300. doi: 10.1172/JCI106608. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Schorr I., Rathnam P., Saxena B. B., Ney R. L. Multiple specific hormone receptors in the adenylate cyclase of an adrenocortical carcinoma. J Biol Chem. 1971 Sep 25;246(18):5806–5811. [PubMed] [Google Scholar]
  30. Sharma R. K., Brush J. S. Metabolic regulation of steroidogenesis in adrenocortical carcinoma cells of rat. Effect of adrenocorticotropin and adenosine cyclic 3',5'-monophosphate on the incorporation of (20S)-20-hydroxy(7 alpha-3H)cholesterol into deoxycorticosterone and corticosterone. Biochem Biophys Res Commun. 1974 Jan;56(1):256–263. doi: 10.1016/s0006-291x(74)80342-6. [DOI] [PubMed] [Google Scholar]
  31. Sharma R. K., Hashimoto K. Ultrastructural studies and metabolic regulation of isolated adrenocortical carcinoma cells of rat. Cancer Res. 1972 Apr;32(4):666–674. [PubMed] [Google Scholar]
  32. Sharma R. K. Metabolic regulation of steroidogenesis in adrenocortical carcinoma cells of rat. Effect of adrenocorticotropin and adenosine cyclic 3':5'-monophosphate on corticosteroidogenesis. Eur J Biochem. 1973 Feb 1;32(3):506–512. doi: 10.1111/j.1432-1033.1973.tb02635.x. [DOI] [PubMed] [Google Scholar]
  33. Sharma R. K. Studies on adrenocortical carcinoma of rat cyclic nucleotide phosphodiesterase activities. Cancer Res. 1972 Aug;32(8):1734–1736. [PubMed] [Google Scholar]
  34. Tesser G. I., Maier R., Schenkel-Hulliger L., Barthe P. L., Kamber B., Rittel W. Biolobical activity of corticotrophin peptides with homo-arginine, lysine or ornithine substituted for arginine in position 8. Acta Endocrinol (Copenh) 1973 Sep;74(1):56–66. doi: 10.1530/acta.0.0740056. [DOI] [PubMed] [Google Scholar]

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