Multiple Hormone Receptors in the Adenylate Cyclase of Human Adrenocortical Tumors1

[CANCER RESEARCH 40, 3768-3771. October 1980] 0008-5472/80/0040-OOOOS02.00 Multiple Hormone Receptors in the Adenylate Cyclase of Human Adrenocortical Tumors1

Shigeru Matsukura,2 Teruo Kakita,3 Satoru Sueoka, Hiroki Yoshimi, Yukio Mirata, Makoto Yokota, and Takuo Fujita

Third Division. Department of Medicine. Kobe University School of Medicine. Ikuta-ku, Kobe 650. Japan

ABSTRACT relate the presence of altered hormone receptors to the pa thology of the human adrenal gland. Adenylate cyclase responses to pituitary hormones including adrenocorticotropic hormone (ACTH), biogenetic amines, pros- MATERIALS AND METHODS taglandin E, (PGE,), angiotensin II, and glucagon were evalu ated in adrenocortical tumors and hyperplastic adrenal tissues, obtained from patients with Cushing's syndrome at surgery, Normal adrenal tissues were obtained at therapeutic total adrenalectomy from 2 patients with breast carcinoma. Two and in normal adrenals. The adenylate cyclase of two normal bilaterally hyperplastic adrenocortical tissues due to excess adrenals was activated only by ACTH and PGEi among the ACTH secretion from the pituitary, 5 clinically ACTH-responsive hormones tested, while that of two hyperplastic adrenal tissues adrenal adenomas, an ACTH-unresponsive carcinoma, and an due to excessive pituitary ACTH secretion was stimulated only ACTH-responsive adrenocortical nodular hyperplastic tissue by ACTH. Of five ACTH-responsive adrenocortical adenomas, were obtained at surgery from patients presenting with clinical in contrast, three were stimulated by norepinephrine, two by and biochemical evidence of Cushing's syndrome (1). The epinephrine, one by thyroid-stimulating hormone, and one by tissue specimens were processed, and the whole homogenates luteinizing hormone in addition to ACTH, indicating the pres were mainly used in duplicate or triplicate for the adenylate ence of multiple receptors for hormones other than ACTH and cyclase assay described in the previous paper (11). In brief, PGEi in these four tumors. The cyclase of an ACTH-unrespon- the adenylate cyclase response was expressed as cyclic AMP sive adrenocortical carcinoma was activated only by PGE, and (pmol/mg protein) produced during 20-min incubation at 37Â° not by other hormones including ACTH, whereas that of an with enzyme fractions and hormones, based on the conversion ACTH-responsive adrenocortical nodular hyperplasia was stim of [14C]ATP to [14C]cyclic AMP. To obtain the fractions, the ulated by ACTH and glucagon but not by other hormones homogenate of an adrenal adenoma (Case 1) was centrifuged including PGE,. at 600 x g for 10 min. The sediment was collected, and the These results indicate the presence of multiple receptors for supernatant was centrifuged at 10,000 x g for 10 min. The hormones other than ACTH and PGE,, the normal adrenocor sedimented particles (600 x g and 10,000 x g) were resus- tical stimulants, in human adrenocortical tumors, particularly in pended in the medium, utilizing volumes adjusted to yield adrenal adenomas, but not in normal and hyperplastic (of approximately equal protein concentrations and used for the whichever an etiology) adrenocortical tissues, suggesting a adenylate cyclase assay. functional alteration of the cellular membrane receptors in ACTH (Cortrosyn) was supplied by Daiichi, Tokyo, Japan; human adrenocortical tumors. PGE, was supplied by Ono, Osaka, Japan; and glucagon was furnished by Novo Industrials, Copenhagen, Denmark. Angio INTRODUCTION tensin II aspartic-/6-amide 5-valine was supplied by Ciba-Geigy, Basel, Switzerland. Ovine or bovine TSH, LH, follicle-stimulat The altered cell surface characteristics distinguishing cancer ing hormone, and prolactin were kindly provided by the Na cells from normal ones (8, 14) are well known. In view of the tional Institute of Arthritis, Metabolism, and Digestive Diseases, initial binding of many hormones to their specific cell surface NIH, Bethesda, Md. Dopamine and serotonin were purchased receptors on their target (6), prior to the action, qualitative from Nakarai, Kyoto, Japan; norepinephrine was supplied by changes of hormone responsiveness may be expected in the Fluka AG, B, Switzerland; and epinephrine was purchased tumors of several endocrine glands (5, 18, 19). The presence from Merck, Darmstadt, West Germany. [8-14C]ATP or [U- of multiple hormone receptors for hormones other than ACTH4 14C]ATP and [3H]cyclic AMP were purchased from New Eng has been demonstrated in the adrenocortical tumors of rats land Nuclear, Boston, Mass. (20, 21) and humans (10). The present investigation was de Statistical analysis was performed by Student's f test. Con signed to investigate further the adenylate cyclase responses sidered significant were p values less than 0.05. of normal, hyperplastic, and tumorous adrenocortical tissues of humans to hormones and other active substances and to RESULTS 1This study was supported by grants from the Ministry of Health and Welfare and the Ministry of Education, Science, and Culture, Japan. '' To whom requests for reprints should be addressed. Adenylate Cyclase of Normal Adrenals. The adenylate cy ' Present address: Endocrine Division. Department of Medicine. Kanazawa clase responses of 2 normal adrenals are shown in Table I. The Medical College, Uchinada-cho. Ishikawa 920-20. Japan. adrenal homogenates possess a cyclase system responsive to " The abbreviations used are: ACTH, adrenocorticotropic hormone; cyclic ACTH, PGE,, and NaF. Other polypeptide hormones and bio- AMP, cyclic adenosine 3':5'-monophosphate; PGE,, prostaglandin E,: TSH, thyroid-stimulating hormone; LH, luteinizing hormone. genetic amines tested were without effect in activating the Received March 6, 1980; accepted June 19, 1980. cyclase.

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Table 1 Table 2 Adenylate cyclase responses of 2 normal adrenal glands Adenylate cyclase responses of 2 bilateral hyperplastic adrenocortical tissues Whole tissue homogenates were incubated with or without the addition of Conditions of the experiment are similar to those described in Table 1. hormones as described in the text. Adenylate cyclase activity is expressed as pmol of cyclic AMP produced per mg of protein per 20 min at 37Â°. Adenylate cyclase activity (cyclic AMP (pmol/mg protein/20 min)| Adenylate cyclase activity Concentra pro-AdditionControlACTHTSHProlactinLHFollicle-stimulatinghormoneEpinephrineNorepinephrineAngiotensin[cyclic AMP (pmol/mg Addition tion (M) Case 1 Case 2 mm)]Case Control Â±2a117 auun 4677 1333*46 ACTHTSHEpinephrineNorepinephrineGlucagonAngiotensin"10 (M)10101010101010102.8 1110a197111929314696119639Case21965042102231742071901962154392071691296Â±Â±Â±Â±Â±Â±Â±iÂ±Â±Â±+26t>13C101371622122457C3814Â± 510 590 250 5io-510 573 253 568 457 "10s2.8 373 956 IIPGE, Â±2100 Â±249 X 10 5 Â± 14 Â±4 99 Â±2b NaF10 10 282 112Â± 4b52Â±3a Mean Â±S.E. of triplicate determinations. 1p < 0.01 (stimulated versus control values).

IIPGE,GlucagonSerotoninNaF^UM^enir x101.2b-410'5-2tein/20 Table 3 x10-Â«-5-5-5-6-5-S-a10 102C Adenylate cyclase responses of whole homogenates and fractionated particles from an adrenocortical adenoma (Case 1) Mean of duplicate determinations. 0 Mean Â±S.E. of triplicate determinations Conditions of the experiment are similar to those described in Table 1 except c p < 0.01 (stimulated versus control values). for use of the particulate fractions for the assay. Adenylate cyclase activity [cyclic AMP (pmol/ min)]AdditionControlACTHEpinephrineNorepinephrineAngiotensinCon- mg protein/20 Adenylate Cyclase of Bilateral Hyperplastic Adrenocorti cal Tissues Due to Excess ACTH Secretion. The adenylate Wholehomog-(M) x g parti xgparticle66 cyclase responses to 2 bilaterally hyperplastic adrenal tissues enate2391010101037639236320710cle99 18a+ +5a176 due to excess ACTH secretion obtained from the patients with +237 37"Â± +279 +16Ã–192 Cushing's disease are shown in Table 2. The adenylate cyclase 25Â°Â± Â±156265 Â±215 14Â°Â± Â±14Â°78 of the hyperplastic tissues was stimulated by ACTH and NaF Â±115 IINaFtration 24Â±1506600Â±1 Â±10327 but not by other hormones. This finding is quite similar to that Â±43o 1450+ 191 Â±19a37"Bb10"1210,000 of normal adrenal tissues except for the failure of activation of Mean Â±S.E. of triplicate determinations. the cyclase of the hyperplastic tissues by PGE,. 1p < 0.05 (stimulated versus control values). Adenylate Cyclase of ACTH-responsive Adrenocortical Ad enomas. The activity of the adenylate cyclase in the whole tissue homogenates and in the 600 x g and 10,000 x g Table 4 particulate fractions from an adrenal adenoma (Case 1) is Adenylate cyclase responses of 3 adrenocortical adenomas shown in Table 3. The cyclase of the homogenate and of each Conditions of the experiment are similar to those described in Table 1. fraction was stimulated by ACTH, epinephrine, norepinephrine, AMPAdditionControlACTHTSHLHEpinephrineNorepinephrineGlucagonAngiotensinAdenylate cyclase activity [cyclic and NaF despite a decrease of the control cyclase levels in the min)]Case protein/20

600 x g and 10,000 x g particulate fractions relative to that 2161 3134b29212410814460108807Case317 in the whole homogenate, thus making the percentage of +12a243 +533 Â±20C240 stimulation over the control greater. The whole homogenate, 'io-5IO'510 Â±330 +45C234 however, was used for the adenylate cyclase assay to ensure +519 Â±2802623248508232654 a rapid and simple processing of the tissues throughout the â€¢io-io-io-52.8 Â±25C159 experiments. The adenylate cyclase activities of 3 other adre Â±4198 nocortical adenomas are shown in Table 4. The tumor adenyl Â±15166 IIPGE,NaFConcentration(M)10 Â±15361Â°Case ate cyclase from Case 2 was activated by ACTH, TSH, epi X10"5^o-^(pmol/mg nephrine, and NaF; that from Case 3 was activated by ACTH Â±427a45d1423"7241938U56U50" and NaF, and that from Case 4 was activated by ACTH, LH, a Mean Â±S.E. of triplicate determinations. Mean of duplicate determinations. angiotensin II, PGE,, and NaF. The cyclase of an homogenate c p < 0.05 (stimulated versus control values). of an adrenocortical adenoma (Case 5) was stimulated by p < 0.01 (stimulated versus control values). ACTH, TSH, norepinephrine, and PGE, in a dose-related man ner (Table 5). The highest concentrations of ACTH and PGE, used for significant stimulation of the adenylate cyclase activity Adenylate Cyclase of an ACTH-unresponsive Adrenocor induced an apparent but statistically insignificant additive effect tical Carcinoma and an ACTH-responsive Primary Nodular on simultaneous addition (Table 5). Epinephrine, which alone Hyperplasia. The cyclase of a clinically ACTH-unresponsive had no effect on the tumor, also failed to affect the cyclase carcinoma was stimulated by PGE, and NaF but not by other stimulation by ACTH on simultaneous addition. hormones including ACTH (Table 6), whereas that of an ACTH- In summary, of 5 adrenocortical adenomas, 3 were stimu responsive (primary) adrenocortical nodular hyperplasia ca lated by norepinephrine, 2 by epinephrine, one by TSH, and pable of secreting corticosteroids autonomously by a still un- one by LH, in addition to ACTH and NaF, indicating the pres clarified mechanism (1, 16) was activated by ACTH, glucagon, ence of multiple hormone receptors in the 4 tumors tested. and NaF (Table 7).

OCTOBER 1980 3769

Table 5 siveness of cyclase of the homogenates of 2 normal human Adeny/ate cyclase responses of an adrenocortical adenoma (Case 5) adrenals only to ACTH and PGE, besides a nonspecific stim Conditions of the experiment are similar to those described in Table 1. ulator, NaF. In contrast, Schorr and Ney (20) and Schorr ef al. cyclase (21) for the first time reported the positive response of the activity [cyclic AMP Concentration (pmol/mg protein/ adenylate cyclase of the homogenates of transplantable rat AdditionControlACTHTSHEpmephrineNorepinephrinePGE,ACTH(M) 20min)]1 adrenocortical carcinoma to several hormones (epinephrine, 8a10-10-10-10-10'10-10"1010-2021701122271461191222221652812 Â± norepinephrine, and TSH) in addition to ACTH, and this was later confirmed by Brush ef al. (4). Hinshaw and Ney (10) also reported the activation of the cyclase by TSH and LH of 2 (one each of adenoma and carcinoma) of 4 human adrenocortical tumors (2 of adenomas and carcinomas). The present study showing the presence of the adenylate cyclase responsive to hormones other than ACTH and PGE, in 4 of the 5 tumors not

20028x 10 5 only confirmed their observations (10) but also demonstrated 16610" X 10 6 the additional activation of the tumor cyclase by norepineph +PGE,ACTH 25810"+ 2.8 X 10s rine, epinephrine, and LH in a dose-related manner (Table 5), + 10'517530Â°11b420b128916b1017"739"7"10 +epinephinreNaFAdenylate 2 241 Â± 3Â° in complete agreement with the results obtained with rat adre a Mean + S.E of triplicate determinations. nal tumors (4, 20, 21). Recently, ectopie /Ã®-adrenergic recep p < 0.05 (stimulated versus control values). tor-binding sites not present in membranes of normal rat ad renal tissues have been demonstrated in the rat adrenocortical carcinoma, indicating a possible molecular basis of the cate- Table 6 Adenylate cyclase responses of an ACTH-unresponsive adrenocortical cholamine sensitivity of the tumor cyclase (26). The ACTH- carcinoma induced cortisol release before surgery in our patients with Conditions of the experiment are similar to those described in Table 1. adenomas is well in accordance with the significant stimulation cyclase activity by ACTH of the adenylate cyclase of each tumor. Furthermore, Concentration [cyclic AMP (pmol/mg our finding of activation of the cyclase by LH but not by TSH in AdditionControlACTHTSHLHEpinephrineNorepinephrinePGE,Angiotensinmin)]10"10(M) protein/20 Â±27a31731233828734847035332986177b21509Case 4 (Table 4) was suggestive of an inappropriate receptor for LH (20, 21) in the human tumor rather than a receptor for "10 TSH contained in the impure LH preparation as proposed by 510"10 Hinshaw and Ney (10). '2.8 Of particular interest is the absence of multiple hormone x 10510 receptors in the adenylate cyclase of 2 hyperplastic adreno IINaFAdenylate 510~2328 Â±18Â° cortical tissues due to excess ACTH secretion, as in the cyclase '' Mean Â±S.E. of triplicate determinations response of normal human adrenals in contrast to adenomas. 13p < 0.01 (stimulated versus control values). Thus, the inappropriate hormone responses in adenomas are probably not a secondary effect of adrenal hyperplasia due to

Table 7 excess ACTH secretion or increased glucocorticoid production Adenylate cyclase responses of an ACTH-responsive primary adrenocortical itself but a result of functional cell surface alterations subse nodular hyperplasia quent to the tumorous transformation with loss of the hormonal Conditions of the experiment are similar to those described in Table 1. specificity of cell surface receptors. The reason for the unre- Adenylate cyclase activ sponsiveness of the cyclase of hyperplastic adrenal tissues to Concentration ity [cyclic AMP (pmol/ PGE, unlike normal adrenals remains obscure. Addition (M) mg protein/20 min)] 13a35Ã’5620144?"6The positive or negative cyclase response to ACTH of an Control i ACTHTSHLHFollicle-stimulatinghormoneDopamine 432182181192165 adrenocortical carcinoma and an adrenocortical nodular hy perplasia was well related to their clinical response to ACTH tested before surgery. As another point of significance in the present study, the adrenal carcinoma which is considered to be more malignant than adenoma appeared to have no inap GlucagonPGE, 102.8 5660 propriate receptors for hormones other than PGE,. This is in X 1 * 153 :456 NaF10101010-10 10191 477 d: accord with the observations of Saez era/. (1 7) on the absence a Mean Â±S.E. of triplicate determinations of receptors for epinephrine, LH, glucagon, and insulin and the b p < 0.01 (stimulated versus control values). presence of those for PGE, in all 4 adrenocortical carcinomas tested, one ACTH responsive and 3 nonresponsive. Saez era/. DISCUSSION (18) also observed no adenylate cyclase responsiveness to norepinephrine, glucagon, and TSH in 5 ACTH-sensitive and 6 Exclusive activation by ACTH and PGE, (7, 10, 17, 18) of ACTH-resistant tumors (histologically not specified). On the the adenylate cyclase of normal adrenal homogenates or par- other hand, Hinshaw and Ney (10) reported the stimulation of ticulate fractions of humans and animals has been well docu the adenylate cyclase of a human adrenocortical carcinoma by mented, while other peptide hormones, biogenetic amines, and TSH and LH in addition to ACTH while Millington ef al. (12) thyroid hormones are without effect (9, 10, 20). These findings observed a feminizing adrenocoritcal carcinoma with the cy are quite in accord with the present data indicating the respon clase responsive to LH, follicle-stimulating hormone, and pro-

3770 CANCER RESEARCH VOL. 40

Downloaded from cancerres.aacrjournals.org on September 24, 2021. © 1980 American Association for Cancer Research. Receptors of Human Adrenocortical Tumors lactin. Whether or not, however, the frequent presence of also thank Dr. M. Inada. Dr. Y. Nakai, and Dr. T. Mori for providing the opportunity multiple hormone receptors is characteristic of the adenoma- to study their patients and S. Yanagihara for expert secretarial assistance. tous rather than carcinomatous changes of human adrenal cortex remains to be elucidated. In the chemical carcinogen- REFERENCES induced liver tumors of the rat, a greater activation of the 1. Besser, G. M., and Edwards, C. R. W. Gushing s syndrome. Clin. Endocrinol. adenylate cyclase by catecholamines has been noted in the Metab., /. 451-490, 1972. 2. Boyd, H.. Louis. C. J.. and Martin. T. J. 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Shigeru Matsukura, Teruo Kakita, Satoru Sueoka, et al.

Cancer Res 1980;40:3768-3771.

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