Adrenocorticotropic Hormone Production Research Articles

Hormone (ACTH, T3) content of immunophenotyped lymphocyte subpopulations.

Cells of the immune system synthesize, store, and secrete polypeptide and amino acid type hormones, which also influence their functions, having receptors for different hormones. In the present experiment immunophenotyped immune cells isolated from bone marrow, thymus, and peritoneal fluid of mice were used for demonstrating the adrenocorticotropic hormone (ACTH) and triiodothyronine (T3) hormone production of differentiating immune cells. Both hormones were found in each cell type, and in each maturation state, which means that all cells are participating in the hormonal function of the immune system. The lineage-independent presence of ACTH and T3 in differentiating hematopoietic cells denotes that their expression ubiquitous during lymphocyte development. Higher ACTH and T3 content of B cells shows that these cells are the most hormonally active and suggests that the hormones may have an autocrine regulatory role in B cell development. Developing T cells showed heterogeneous hormone production which was associated with their maturation state. Differences in the hormone contents of immune cells isolated from different organs indicate that their hormone production is defined by their differentiation or maturation state, however, possibly also by the local microenvironment.

E2F1-mediated human POMC expression in ectopic Cushing's syndrome.

Cushing's syndrome is caused by excessive adrenocorticotropic hormone (ACTH) secretion derived from pituitary corticotroph tumors (Cushing disease) or from non-pituitary tumors (ectopic Cushing's syndrome). Hypercortisolemic features of ectopic Cushing's syndrome are severe, and no definitive treatment for paraneoplastic ACTH excess is available. We aimed to identify subcellular therapeutic targets by elucidating transcriptional regulation of the human ACTH precursor POMC (proopiomelanocortin) and ACTH production in non-pituitary tumor cells and in cell lines derived from patients with ectopic Cushing's syndrome. We show that ectopic hPOMC transcription proceeds independently of pituitary-specific Tpit/Pitx1 and demonstrate a novel E2F1-mediated transcriptional mechanism regulating hPOMC We identify an E2F1 cluster binding to the proximal hPOMC promoter region (-42 to +68), with DNA-binding activity determined by the phosphorylation at Ser-337. hPOMC mRNA expression in cancer cells was upregulated (up to 40-fold) by the co-expression of E2F1 and its heterodimer partner DP1. Direct and indirect inhibitors of E2F1 activity suppressed hPOMC gene expression and ACTH by modifying E2F1 DNA-binding activity in ectopic Cushing's cell lines and primary tumor cells, and also suppressed paraneoplastic ACTH and cortisol levels in xenografted mice. E2F1-mediated hPOMC transcription is a potential target for suppressing ACTH production in ectopic Cushing's syndrome.

Frequency of Cushing\u2019s syndrome due to ACTH-secreting adrenal medullary lesions: a retrospective study over 10 years from a single center

Cushing’s syndrome due to ectopic adrenocorticotropic hormone production from adrenal medullary lesions has occasionally been described. We retrospectively reviewed all 164 cases of Cushing’s syndrome and 77 cases of pheochromocytomas during 10 years. Of all cases with Cushing’s syndrome, only two cases (1.2 %) were due to ectopic adrenocorticotropic hormone production from adrenal medullary lesions (one case of pheochromocytoma and one case of adrenal medullary hyperplasia). Of all pheochromocytomas only the above-mentioned case (1.3 %) also gave rise to an ectopic adrenocorticotropic hormone syndrome. The clinical presentation of adrenocorticotropic hormone-secreting pheochromocytoma and adrenal medullary hyperplasia can be anything from mild to dramatic. These are rare conditions important to bear in mind in the workup of a patient with Cushing’s syndrome or with pheochromocytoma. The identification of ectopic adrenocorticotropic hormone secretion from adrenal medullary lesions can be life-saving.

Increasing Skin Pigmentation Following Severe Head Trauma: All That Glitters Is Not Gold!

We report the case of a 67-year-old man who was admitted to our Intensive Care Unit because of traumatic brain injury. During his prolonged hospitalization, gradual darkening of the skin all over his body was observed. An excess corticotropin (ACTH) production syndrome was considered. The patient’s hormone study showed high levels of ACTH (978 pg/ml) with normal cortisol levels. Extensive clinical and laboratory investigations revealed adenocarcinoma of the colon, which was likely the site of the ectopic ACTH production. This is a very rare manifestation of paraneoplastic syndrome during the course of colon adenocarcinoma. The most important feature of this case report is that this rare syndrome was accidentally discovered, in a patient hospitalized for unrelated reasons, by simple clinical investigation.LEARNING POINTSCareful physical examination can provide valuable information which can lead to the diagnosis of rare and unexpected syndromes.Common clinical wisdom says that all signs and symptoms must fit one diagnosis, but in some cases there is more than one diagnosis.

Inhibition of Ubiquitin-specific Peptidase 8 Suppresses Adrenocorticotropic Hormone Production and Tumorous Corticotroph Cell Growth in AtT20 Cells.

Background:Two recent whole-exome sequencing researches identifying somatic mutations in the ubiquitin-specific protease 8 (USP8) gene in pituitary corticotroph adenomas provide exciting advances in this field. These mutations drive increased epidermal growth factor receptor (EGFR) signaling and promote adrenocorticotropic hormone (ACTH) production. This study was to investigate whether the inhibition of USP8 activity could be a strategy for the treatment of Cushing's disease (CD).Methods:The anticancer effect of USP8 inhibitor was determined by testing cell viability, colony formation, apoptosis, and ACTH secretion. The immunoblotting and quantitative reverse transcription polymerase chain reaction were conducted to explore the signaling pathway by USP8 inhibition.Results:Inhibition of USP8-induced degradation of receptor tyrosine kinases including EGFR, EGFR-2 (ERBB2), and Met leading to a suppression of AtT20 cell growth and ACTH secretion. Moreover, treatment with USP8 inhibitor markedly induced AtT20 cells apoptosis.Conclusions:Inhibition of USP8 activity could be an effective strategy for CD. It might provide a novel pharmacological approach for the treatment of CD.

Functional morphology of pituitary -thyroid and -adrenocortical axes in middle-aged male rats treated with Vitex agnus castus essential oil

We previously reported that Vitex agnus-castus L. essential oil (VACEO), when administered to middle-aged males, exerts a bone-protective effect, induces silencing of locomotor activities and decreases pituitary prolactin immunopositivity. To further assess the putative endocrine effects of VACEO, we examined the pituitary-thyroid and -adrenocortical axes in our model. Sixteen-month-old Wistar rats were subcutaneously administered 60mg/kg of VACEO dissolved in sterile olive oil, while the control group received the same amount of vehicle alone for three weeks. Pituitaries, thyroids and adrenals were analyzed by qualitative and quantitative histological approaches. Concentration of thyroid stimulating hormone (TSH), total thyroxine and triiodothyronine (TH), adrenocorticotrophic hormone (ACTH), corticosterone in serum and in adrenal tissue were measured. In VACEO-treated rats, the relative volume density of pituitary thyrotrophs increased (p<0.001), while intensity of cytoplasmic TSHβ immunostaining decreased (p<0.001), consistent with elevated TSH in serum (p<0.01). The thyroid tissue was characterized by a micro-follicular structure, increased relative volume of follicular epithelium (p<0.05), decreased volume of luminal colloid (p<0.001) and increased basolateral expression of sodium-iodide symporter-immunopositivity (p<0.05). Serum TH also increased (p<0.01). The relative volume density of pituitary corticotrophs decreased (p<0.05), compatible with decline in circulating ACTH (p<0.05). Neither tissue nor serum corticosterone levels were affected by VACEO treatment. In conclusion, the observed changes in TSH and ACTH strongly indicate central endocrine effects of prolonged VACEO treatment. In this respect, production of ACTH decreased without impact on corticosterone production. Increase in serum concentration of both TH and TSH are not compatible with a negative feedback loop and suggest a major change in set-point regulation of the hypothalamic-pituitary-thyroid axis.

Pubertal Development

Pubertal Development

The landscape of bilateral adrenal incidentalomas associated with subclinical hypercortisolism

Since the first report of a “subclinical” Cushing’s syndrome dated back to the early 1970s [1], a great deal of effort has been put to understand the molecular pathogenesis and the clinical correlates of this condition. Despite the exponential number of publications over the last years, it is still difficult to draw definitive conclusions on the clinical impact of incidentally diagnosed hypercortisolism, not associated with a clear Cushing’s phenotype. As every physician involved in the management of adrenal diseases knows, the main source of uncertainty resides in the definition of this pathological condition, which generates difficulties in achieving comparable results among different studies, and the lack of well-designed prospective studies covering a long time span, leading to difficulties in estimating the prevalence of cortisol-associated comorbidities and longterm consequences. However, keeping in mind those limitations, evidence from long-term retrospective studies has indirectly shown that a mild, but sustained, cortisol hypersecretion can be related to an increased risk of cardiovascular and metabolic correlates, which seems to be related to the cortisol secretion, as well as to the progressive secreting pattern over time [2–4]. Most of the studies on long-term consequences are focused on unilateral adrenocortical tumors, which represent the most frequent entity in radiological series. Lately, an increasing number of studies have been focused on the analysis of hormonal and clinical characteristics of bilateral incidentalomas, raising attention to the difficulties of the clinical management of those tumors. The recent advances in the biology of cortisol-secreting tumors have also shed light on the molecular events underlying bilateral adrenocortical tumors, which can be very different from their unilateral counterpart and involve novel pathogenic pathways and previously unknown regulatory mechanisms. The discovery of mutations in the ARMC5 gene in a substantial number of patients with bilateral adrenal hyperplasia and hypercortisolism [5] has broadened the view on the molecular mechanisms underlying adrenocortical hyperplasia, adding an important piece of knowledge to our understanding of tumorigenesis and hormonal hypersecretion in adrenal tumors. Research on aberrant receptors and paracrine regulation of cortisol secretion has provided evidence that the pathophysiology of bilateral masses can be extremely complex. According to the results of in vivo and in vitro studies, the presence of illegitimate receptors is indeed a frequent event among patients with bilateral adrenocortical hyperplasia, with a prevalence that rises up to 87 % [6]. Moreover, after the first pioneering studies [7], the discovery of intra-adrenal adrenocorticotropic hormone (ACTH) production in a substantial number of patients with hypercortisolism [8] has completely changed the knowledge on the feedback mechanisms involved in adrenal steroidogenesis. The review published by Paschou and colleagues [9] was aimed to investigate the relationship between morphological characteristics of the adrenal glands and the secretory pattern, with focus on incidentally discovered adrenocortical tumors and subclinical hypercortisolism. Based on the data provided by six studies published between 2011 and 2015, the main finding of the review is that the overall prevalence of subclinical hypercortisolism is increased in bilateral adrenal incidentalomas vs. unilateral adenomas. Surprisingly, the * Guido Di Dalmazi Guido.Di_Dalmazi@med.uni-muenchen.de gdd1982@gmail.com

Neuroendocrine carcinoma of the ampulla of Vater causing ectopic adrenocorticotropic hormone-dependent Cushing's syndrome.

Ectopic adrenocorticotropic hormone (ACTH) is rarely secreted by neuroendocrine tumors. Although neuroendocrine tumors may occur at any site in the gastrointestinal system, they very rarely occur in the ampulla of Vater and have a poor prognosis. The present study described the first Cushing's syndrome as a result of ectopic ACTH arising from the ampulla of Vater neuroendocrine carcinoma. A 69-year-old female was admitted with clinical features of Cushing's syndrome, confirmed biochemically by hypokalemia, and elevated levels of ACTH and cortisol. In further investigations, a tumor of the ampulla of Vater and liver metastases were detected. Pathological analysis of the biopsy confirmed a neuroendocrine carcinoma, which was immunohistochemically positive for chromogranin A, synaptophysin, cluster of differentiation 56 and ACTH. Therefore, the present study diagnosed a functional and metastatic neuroendocrine carcinoma of the ampulla of Vater with ectopic ACTH production causing Cushing's syndrome. The patient succumbed to mortality 4 months later, despite administration of combined chemotherapy with irinotecan and cisplatin.

60 YEARS OF POMC: Adrenal and extra-adrenal functions of ACTH.

The pituitary adrenocorticotropic hormone (ACTH) plays a pivotal role in homeostasis and stress response and is thus the major component of the hypothalamo-pituitary-adrenal axis. After a brief summary of ACTH production from proopiomelanocortin (POMC) and on ACTH receptor properties, the first part of the review covers the role of ACTH in steroidogenesis and steroid secretion. We highlight the mechanisms explaining the differential acute vs chronic effects of ACTH on aldosterone and glucocorticoid secretion. The second part summarizes the effects of ACTH on adrenal growth, addressing its role as either a mitogenic or a differentiating factor. We then review the mechanisms involved in steroid secretion, from the classical Cyclic adenosine monophosphate second messenger system to various signaling cascades. We also consider how the interaction between the extracellular matrix and the cytoskeleton may trigger activation of signaling platforms potentially stimulating or repressing the steroidogenic potency of ACTH. Finally, we consider the extra-adrenal actions of ACTH, in particular its role in differentiation in a variety of cell types, in addition to its known lipolytic effects on adipocytes. In each section, we endeavor to correlate basic mechanisms of ACTH function with the pathological consequences of ACTH signaling deficiency and of overproduction of ACTH.

Desmoplastic nested spindle cell tumours and nested stromal epithelial tumours of the liver.

Desmoplastic nested spindle cell tumour of liver (DNSTL), nested stromal-epithelial tumour (NSET) and calcifying nested stromal-epithelial tumour (CNSET) are recently described entities with similar morphology, immunohistochemistry and molecular genetics. These are rare entities with only three large case series described till date. These tumours commonly present in the paediatric age group. NSETs, in addition have been described to be associated with ectopic adrenocorticotropic hormone (ACTH) production and Cushingoid features. It is important to discuss this rare group of tumours with a low malignant potential as the most common radiological differential diagnosis is hepatoblastoma, which has a relatively poorer prognosis. Thus, a pathologist needs to keep this entity in mind, so as to offer a correct histological diagnosis.

Nur77 gene expression levels were involved in different ACTH-secretion autonomy between Cushing's disease and subclinical Cushing's disease.

Cushing's disease (CD) and subclinical Cushing's disease (subCD) are both diseases caused by adrenocorticotropic hormone (ACTH)-secreting pituitary adenomas. However, ACTH autonomy in subCD is weaker than in CD and there are no Cushingoid features in subCD. The differences of molecular mechanisms in ACTH autonomy between CD and subCD have not yet been reported. Therefore, we aimed to investigate the differences in molecular mechanisms of ACTH-secretion autonomy between CD and subCD. The study included 23 patients [7 CD, 6 subCD, and 10 non-functioning pituitary tumors (NFTs)] who underwent transsphenoidal surgery at the Osaka University Hospital between December 2009 and October 2013. Using quantitative real-time PCR, various ACTH-related gene expressions in tumor tissues from CD, subCD, and NFT were measured such as pro-opiomelanocortin (POMC), POMC transcription factor (Tpit, Pitx1, NeuroD1, and Nur77), POMC peptide processing enzymes (prohormone convertase: PC1/3 and PC2), and ACTH secretion-related factors (corticotropin-releasing hormone receptor 1: CRHR1 and glucocorticoid receptor α: GRα). Only Nur77 mRNA levels were significantly higher in CD than in subCD. Furthermore, we stained 6 CD and 6 subCD with anti-Nur77 antibody. All tumor samples from CD had Nur77 protein positive cells. On the other hand, Nur77 protein was expressed in only one tumor sample from subCD. This sample showed high expression of Nur77 mRNA. Nur77 is an important to regulate POMC transcription and negative-feedback by glucocorticoids. Nur77 gene expression levels might involve different autonomy of ACTH production between CD and subCD.

Bilateral inferior petrosal sinus sampling using vasopressin

Context:Anatomical localization of pituitary adenoma can be challenging in adrenocorticotropic hormone (ACTH)-dependent Cushing's syndrome, and bilateral inferior petrosal sinus sampling (BIPSS) is considered gold standard in this regard. Stimulation using corticotrophin-releasing hormone (CRH) improves the sensitivity of BIPSS, however, same is not easily available in India. Therefore, we undertook this study of BIPPS using vasopressin as agent for stimulation owing to its ability to stimulate V3 receptors present on corticotrophs.Aims:To study the tumor localization and lateralization in difficult to localize cases of ACTH-dependent Cushing's syndrome by bilateral inferior petrosal sinus sampling using vasopressin for corticotroph stimulation.Settings and Design:Prospective observational study.Subjects and Methods:Six patients (5 females) meeting inclusion criteria underwent BIPSS using vasopressin for stimulation.Results:All six patients had nonsuppressible overnight and low dose dexamethasone suppression test with elevated plasma ACTH levels suggestive of ACTH-dependent Cushing's syndrome. High dose dexamethasone suppression test showed suppressible cortisol in two cases, and microadenoma was seen in two patients on magnetic resonance imaging pituitary. Contrast enhanced computed tomography of the abdomen showed left adrenal hyperplasia in one case and anterior mediastinal mass with bilateral adrenal hyperplasia another. Using BIPSS four patients were classified as having Cushing's disease that was confirmed histopathologically following surgery. Of the remaining two, one had primary pigmented nodular adrenocortical disease, and another had thymic carcinoid with ectopic ACTH production as the cause of Cushing's syndrome. No serious adverse events were noted.Conclusions:Vasopressin may be used instead of CRH and desmopressin for stimulation in BIPSS.

Etiopathogeny of Primary Adrenal Hypercortisolism.

Primary adrenal hypercortisolism is mainly due to cortisol-producing adrenocortical adenomas, bilateral micronodular or macronodular disease, and adrenal carcinomas. Important advances in the pathophysiology of primary adrenal hypercortisolism have been made in the last few years, partly through the use of new molecular biology tools. Most adrenal abnormalities leading to increased cortisol production involve somatic or germinal mutations of genes encoding elements of the cyclic AMP/protein kinase A signaling pathway, as shown in adrenal adenomas in 2014. One peculiar condition is primary macronodular adrenal hyperplasia (PMAH), which has given rise to new pathophysiological concepts such as regulation of cortisol secretion by illegitimate ligands through aberrant expression of G protein-coupled transmembrane receptors in adrenal nodules and stimulation of cortisol production by local adrenocorticotropic hormone production through autocrine/paracrine mechanisms. These findings provide a basis for the development of targeted therapies as an alternative to surgery. The recent identification of germinal mutations of ARMC5 in PMAH raises the possibility that this is much more frequently an inherited disease than previously suspected. It also offers the possibility of earlier diagnosis of PMAH by genetic screening and, hopefully, of earlier intervention to prevent the onset of hypercortisolism and its complications. The pathophysiology of Cushing's syndrome associated with a subset of adrenal adenomas, including subclinical cortisol-secreting incidentalomas and adrenal carcinomas, remains to be determined.

The influence of chronic psycho-emotional stress on cognitive function

Aim. The influence of the chronic psycho-emotional stress on the cognitive function was studied.&#x0D; Methods. 160 railroad engineers of main-line locomotives, whose occupation is acknowledged to be one of the most stressful, were examined. 100 healthy volunteers were examined as a control group. A scale of psychological tension PSM-25 was used to evaluate the effect of the stress. Neurohumoral response to stress was studied by the activity of the hypothalamic-pituitary-adrenal axis, defining adrenocorticotropic hormone, cortisol and corticosterone concentrations. Cognitive functions were examined by the neuropsychological tests: Schulte tables, F. Grobov tables, Burdon correction tests. Attention assessment was emphasized due to railroad engineer’s profession specifics. Result. The reaction of the hypothalamic-pituitary-adrenal axis depended on the duration of chronic psycho-emotional stress: resistance period with reduced levels of the stress hormones in the next 5-7 years replaced the period of activation in the first years (with increased production of adrenocorticotropic hormone, cortisol and corticosterone). The reactivation of the hypothalamic-pituitary-adrenal axis occurred after 12-15 years. Neuropsychological tests revealed that the effect of chronic psycho-emotional stress was accompanied by decreased cognitive functions compared to controls. Time for passing the tests and the number of errors increased, productivity, stability and attention concentration dropped. The term of cognitive function disorders onset and their severity depend on chronic psycho-emotional stress duration. The extract of Ginkgo biloba (EGb 761, 240 mg per day for three months) intake has significantly improved the results of neuropsychological retests.&#x0D; Conclusion. Chronic psycho-emotional stress leads to deterioration of cognitive functions, and, in particular, attention. The use of Ginkgo biloba (EGb 761) extract is rational for treatment of cognitive malfunction.

Improvement of kidney yang syndrome by icariin through regulating hypothalamus-pituitary-adrenal axis.

To investigate whether Epimedium brevicornu Maxim (EB) and icariin could exert their protective effects on hydrocortisone induced (HCI) rats by regulating the hypothalamus-pituitary-adrenal (HPA) axis and endocrine system and the possible mechanism. Male 10-week-old Sprague Dawley (SD) rats were allotted to 6 groups (A-F) with 12 each, group A was injected normal saline (NS) 3 mL/kg day intraperitoneally, group A and B were given NS 6 mL/kg day by gastrogavage, group B-F were injected hydrocortisone 15 mg/kg intraperitoneally, group C and D were given EB 8 or 5 g/(kg day) by gastrogavage, group E and F were given icariin 25 or 50 mg/(kg day) by gastrogavage. Gene expressions of hypothalamus corticotropin releasing hormone (CRH) and pituitary proopiomelanocortin (POMC) were detected by reverse transcription-polymerase chain reaction (RT-PCR), and protein of pituitary POMC by Western-blot. The serum T4, testosterone, cortisol and POMC mRNA expression were increased after treatment with EB or icariin in HCI rats, the serum CRH and the hypothalamus CRH mRNA expression released from hypothalamus corticotropin decreased compared with group B (P<0.05).The treatment with only icariin increased serum adrenocorticotropic hormone (ACTH) compared with group B (P<0.05). EB and icariin might be therapeutically beneficial in the treatment of HCI rats through attuning the HPA axis and endocrine system which was involved in the release of CRH in hypothalamic, and the production of POMC-derived peptide ACTH in anterior pituitary, the secretion of corticosteroids in adrenal cortex.

Recurrent gain-of-function USP8 mutations in Cushing's disease.

Cushing's disease, also known as adrenocorticotropic hormone (ACTH)-secreting pituitary adenomas (PAs) that cause excess cortisol production, accounts for up to 85% of corticotrophin-dependent Cushing's syndrome cases. However, the genetic alterations in this disease are unclear. Here, we performed whole-exome sequencing of DNA derived from 12 ACTH-secreting PAs and matched blood samples, which revealed three types of somatic mutations in a candidate gene, USP8 (encoding ubiquitin-specific protease 8), exclusively in exon 14 in 8 of 12 ACTH-secreting PAs. We further evaluated somatic USP8 mutations in additional 258 PAs by Sanger sequencing. Targeted sequencing further identified a total of 17 types of USP8 variants in 67 of 108 ACTH-secreting PAs (62.04%). However, none of these mutations was detected in other types of PAs (n = 150). These mutations aggregate within the 14-3-3 binding motif of USP8 and disrupt the interaction between USP8 and 14-3-3 protein, resulting in an elevated capacity to protect EGFR from lysosomal degradation. Accordingly, PAs with mutated USP8 display a higher incidence of EGFR expression, elevated EGFR protein abundance and mRNA expression levels of POMC, which encodes the precursor of ACTH. PAs with mutated USP8 are significantly smaller in size and have higher ACTH production than wild-type PAs. In surgically resected primary USP8-mutated tumor cells, USP8 knockdown or blocking EGFR effectively attenuates ACTH secretion. Taken together, somatic gain-of-function USP8 mutations are common and contribute to ACTH overproduction in Cushing's disease. Inhibition of USP8 or EGFR is promising for treating USP8-mutated corticotrophin adenoma. Our study highlights the potentially functional mutated gene in Cushing's disease and provides insights into the therapeutics of this disease.

62-Year-Old Man With Persistent Postoperative Nausea and Vomiting

dicine, te ester, visor tant in linic, .). A 62-year-old man with a history of type 2 diabetes mellitus, hypogonadotropic hypogonadism (diagnosed 6 months before presentation), stage 3 chronic kidney disease, and coronary artery disease was admitted to the hospital for treatment ofmitral valve endocarditis. Broad-spectrum antibiotics, including vancomycin and rifampin, were initiated, and in addition, he underwent mitral valve replacement because of vegetations causing severe valvular stenosis. On hospital admission and initiation of broad-spectrum antibiotics, progressive nausea, vomiting, fatigue, and anorexia developed. These symptoms persisted for up to 15 days postoperatively. The symptoms were constant and not necessarily postprandial. He also had fevers and chills, but these symptoms resolved with antibiotic therapy. He reported no abdominal pain and had no history of abdominal surgery. His bowel movements remained regular. The patient had no symptoms of gastroesophageal reflux, headaches, or vertigo. His diabetes was recently diagnosed and was controlled with diet. His symptoms continued despite maximum doses of antiemetics. He had not had similar symptoms before the current episode. Vital signs on evaluation included a temperature of 37.1 C, heart rate of 65 beats/ min, blood pressure of 138/73 mm Hg, and oxygen saturation of 96% while breathing room air. On physical examination, the patient was cachexic and had generalized nonfocal weakness. His body mass index was 19 kg/m. His abdomen was soft, nondistended, and nontender, and normal bowel sounds were present. He had no rashes or lower extremity edema.

Ectopic Adrenocorticotropin Production in a Patient with Lung Cancer: A Case Report

Ectopic Adrenocorticotropin Production in a Patient with Lung Cancer: A Case Report

Aphidicolin inhibits cell proliferation via the p53-GADD45β pathway in AtT-20 cells.

Cushing's disease is primarily caused by pituitary corticotroph adenomas, which autonomically secrete adrenocorticotropic hormone (ACTH). ACTH production may be associated with tumor cell proliferation; however, the effects of cell cycle progression on ACTH production and cell proliferation are little known in corticotroph tumor cells. A DNA polymerase inhibitor, aphidicolin, arrests cells at the entrance to the S phase and blocks the cell cycle; aphidicolin also induces apoptosis in tumor cells. In the present study, we determined ACTH production and cell proliferation of AtT-20 corticotroph tumor cells following treatment with aphidicolin. Aphidicolin decreased proopiomelanocortin mRNA levels in AtT-20 cells and the levels of ACTH in the culture medium of these cells. Aphidicolin also decreased cell proliferation and induced apoptosis in AtT-20 cells. Fluorescence-activated cell sorting analyses revealed that this agent increased the percentage of G0/G1 phase cells, and decreased S phase cells. Aphidicolin decreased the phosphorylation of cyclic adenosine monophosphate response element-binding protein and Akt. Aphidicolin increased the levels of tumor protein 27 (p27) and 53 (p53), while it decreased cyclin E levels. Aphidicolin also increased the mRNA levels of the stress response gene growth arrest and DNA damage-inducible 45β (GADD45β), a putative downstream target of p53. The p53 knockdown increased GADD45β mRNA levels. The GADD45β knockdown inhibited the decreases in cell proliferation. Thus, aphidicolin inhibits cell proliferation via the p53-GADD45β pathway in AtT-20 cells.