Differential Expression of Parathyroid Hormone–Related Protein in Adrenocortical Tumors: Autocrine/Paracrine Effects on the Growth and Signaling Pathways in H295R Cells

Rizk-Rabin, Marthe; Assié, Guillaume; René-Corail, Fernande; Perlemoine, Karine; Hamzaoui, Hinda; Tissier, Frédérique; Lieberherr, Michèle; Bertagna, Xavier; Bertherat, Jérôme; Bouizar, Zhor

doi:10.1158/1055-9965.epi-07-2924

Cited by 26 publications

(29 citation statements)

References 46 publications

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“…While the PTH-related peptide (PTH-rP), a mediator of cancer hypercalcemia that also acts on type 1 PTH receptor, was reported to exert a proliferogenic effect in human adrenocortical carcinoma cells, 32 there are at present no data on whether chronic hyperparathyroidism can exert a proliferogenic effect of the human adrenocortical zona glomerulosa. Hence, this issue deserves specific research efforts.…”

Section: Discussionmentioning

confidence: 99%

Primary Hyperparathyroidism With Concurrent Primary Aldosteronism

et al. 2011

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P rimary aldosteronism (PA) is a common cause of secondary hypertension, because it involves 11.2% of referred hypertensive patients. 1 Primary hyperparathyroidism (PPTH) is much less common, with a prevalence that, albeit imprecisely known, is probably Ͻ0.01% in unselected hypertensives. However, arterial hypertension develops in the majority (56% to 80%) of the PPTH patients, 2 which can explain why they are held to be at increased risk for cardiovascular complications and death. 3 The association of PPTH with arterial hypertension and increased cardiovascular risk would appear to be paradoxical, inasmuch as the parathyroid hormone (PTH) has been described to induce vasodilation through endothelium-independent mechanisms. 4 Therefore, it would be expected to lower rather than to raise blood pressure. 5 The mechanisms by which excess PTH increases blood pressure remained obscure until Mazzocchi et al 6 reported that PTH stimulates in vitro the secretion of aldosterone from human adrenocortical cells in a concentrationdependent manner. These findings suggested that PTH acts as an aldosterone secretagogue that might be involved in causing human PA. However, whether this mechanism, although appealing, could be involved in causing human PA and might explain the development of arterial hypertension in patients with PPTH remained unsupported by any clinical data.We herein report on a patient who presented with resistant arterial hypertension and was found to have PA. Unilateral adrenalectomy resulted in cure of the PA and control of blood pressure despite a tapering of antihypertensive treatment, but the patient developed hyperparathyroidism caused by a PTHsecreting adenoma that was surgically removed. Gene expression and immunohistochemistry studies unveiled the expression of type 1 PTH receptor in the aldosterone-producing adrenocortical nodules and of the mineralocorticoid receptor (MR) in the nuclei of parathyroid adenoma cells. This latter finding was confirmed in a series of normal human parathyroid glands. Thus, this unique case and the related findings support the notion that undetected hyperfunctioning of the parathyroid gland can contribute to maintaining hyperaldosteronism in PA. It also suggests the existence of a bidirectional link between the adrenocortical zona glomerulosa and the parathyroid gland, which can be relevant for the regulation of calcium metabolism and blood pressure. CaseA 68-year-old man was referred for chest pain and resistant hypertension (Figure 1). The patient had a 10-year history of hypertension, which had become resistant to therapy with atenolol at 100 mg, amlodipine at 10 mg, doxazosin at 4 mg, potassium canrenoate at 25 mg, hydrochlorothiazide at 12.5 mg, and telmisartan at 80 mg daily. He had a family history of primary (essential) hypertension and a personal history of previous cigarette smoking, dyslipidemia, paroxysmal atrial fibrillation, and coronary artery disease that was treated with percutaneous transluminal coronary angioplasty and stenting 2 years before. Physical...

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Section: Discussionmentioning

confidence: 99%

Primary Hyperparathyroidism With Concurrent Primary Aldosteronism

et al. 2011

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“…The PepTag Non-Radioactive Protein Kinase Assay kit (Promega) was used to measure the activity of PKA, as previously described (30). Animals and treatments.…”

Section: Methodsmentioning

confidence: 99%

“…Apoptotic cell distribution was analyzed by flow cytometry using a FACScan (Epics XL Coulter) as previously described (30).…”

Section: Methodsmentioning

confidence: 99%

Inactivation of the Carney Complex Gene 1 (Protein Kinase A Regulatory Subunit 1A) Inhibits SMAD3 Expression and TGFβ-Stimulated Apoptosis in Adrenocortical Cells

et al. 2009

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The cyclic AMP signaling pathway can be altered at multiple levels in endocrine tumors. Its central component is the protein kinase A (PKA). Carney complex (CNC) is a hereditary multiple neoplasia syndrome resulting from inactivating mutations of the gene encoding the PKA type I A regulatory subunit (PRKAR1A). Primary pigmented nodular adrenocortical disease is the most frequent endocrine tumor of CNC. Transforming growth factor B (TGFB) regulates adrenal cortex physiology and signals through SMAD2/3. We used an interference approach to test the effects of PRKAR1A inactivation on PKA and TGFB pathways and on apoptosis in adrenocortical cells. PRKAR1A silencing stimulates PKA activity and increases transcriptional activity of a PKA reporter construct and expression of the endogenous PKA target, NR4A2, under basal conditions or after forskolin stimulation. PRKAR1A inactivation also decreased SMAD3 mRNA and protein levels via PKA, altering the cellular response to TGFB. SMAD3 expression was also inhibited by adrenocorticorticotropic hormone in the mouse adrenal gland and by forskolin in H295R cells. TGFB stimulates apoptosis in H295R cells, and this effect was counteracted by PRKAR1A inactivation. PRKAR1A silencing decreased the percentage of apoptotic cells and the cleavage of apoptosis mediators [caspase-3, poly(ADP-ribose) polymerase, and lamin A/C]. Inactivating mutations of PRKAR1A observed in adrenocortical tumors alter SMAD3, leading to resistance to TGFBinduced apoptosis. This cross-talk between the PKA and the TGFB signaling pathways reveals a new mechanism of endocrine tumorigenesis. [Cancer Res 2009;69(18):7278-84]

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“…14 The PTH-related peptide, a mediator of cancer hypercalcemia that also acts on the type 1 PTH receptor, was also reported to stimulate aldosterone 13,15 and to induce proliferation of human adrenocortical carcinoma cells. 16 Furthermore, infusion of aldosterone in rats caused an increase of PTH, thus suggesting a cause-effect relationship between hyperaldosteronism and hyperparathyroidism. 17 The observations that in patients with primary hyperparathyroidism: (1) plasma aldosterone and PTH concentrations were positively correlated; (2) at multivariate analysis, preoperative PTH was an independent predictor of plasma aldosterone concentration; (3) PTH levels Ͼ100 ng/L were an independent predictor of abnormally elevated plasma aldosterone concentration, 18 are also consistent with the concept that PTH plays a role in triggering or maintaining aldosterone secretion in vivo.…”

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confidence: 99%

Hyperparathyroidism Can Be Useful in the Identification of Primary Aldosteronism Due To Aldosterone-Producing Adenoma

et al. 2012

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Abstract-Hyperparathyroidism represents as a novel feature of primary aldosteronism (PA). Its occurrence in patients with the surgically correctable aldosterone-producing adenoma (APA) and not in those with bilateral adrenal hyperplasia suggested that the measurement of parathyroid hormone could help in differentiating between these subtypes of PA. To test this hypothesis we measured the plasma levels of intact parathyroid hormone, Ca 2ϩ , and several markers of calcium/phosphorus metabolism in 132 hypertensive patients, including 74 with primary (essential) hypertension and 58 consecutive PA patients. Of the latter, 46 were conclusively diagnosed as APA (by finding of lateralized aldosterone excess, pathology, correction of the hyperaldosteronism, and evidence of a fall of blood pressure after adrenalectomy) and 12 as bilateral adrenal hyperplasia. Based on these diagnoses we used the area under the receiver operator characteristic curve analysis to assess the accuracy of serum parathyroid hormone for identifying the PA cases in the whole group and for distinguishing between APA and bilateral adrenal hyperplasia. In this selected population of hypertensive patients for identifying PA cases, the accuracy of serum parathyroid hormone tended to be lower than that of the aldosterone:renin ratio. However, for discriminating between APA and bilateral adrenal hyperplasia patients it was better than that under the identity line and also that for the aldosterone:renin ratio for pinpointing APA cases among patients with PA. Hence, these findings indicate that raised serum parathyroid hormone levels are a feature of APA that can be useful for selecting the PA patients to be submitted to adrenal vein sampling. (Hypertension. 2012;60:431-436.) Key Words: aldosterone Ⅲ mineralocorticoids Ⅲ PTH Ⅲ endocrine hypertension Ⅲ secondary hypertension Ⅲ aldosterone-producing adenoma Ⅲ diagnosis Ⅲ calcium I n patients with primary aldosteronism (PA), the discrimination between the surgically curable aldosterone-producing adenoma (APA) and the medically treatable bilateral adrenal hyperplasia (BAH) is a challenging task that usually requires adrenal vein sampling, 1 a minimally invasive, risky, expensive, and not widely available procedure. Accordingly, there is an unmet need of a better strategy for selecting patients more likely to have an APA to be submitted to adrenal vein sampling (AVS). After the pilot reports of secondary hyperparathyroidism in patients with PA 2,3 and also with secondary aldosteronism attributed to congestive heart failure, 4-6 we and others recently documented an elevation of serum parathyroid hormone (PTH) levels in large cohorts of patients with confirmed PA. 7,8 These observations are of great interest given the adverse cardiovascular consequences of excess PTH, which is now appreciated as a cardiovascular risk factor, 9,10 and also because of the evidence that PTH can exert a secretagogue effect on aldosterone. In vitro studies consistently showed that PTH concentration-dependently increases aldosterone in...

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Differential Expression of Parathyroid Hormone–Related Protein in Adrenocortical Tumors: Autocrine/Paracrine Effects on the Growth and Signaling Pathways in H295R Cells

Cited by 26 publications

References 46 publications

Primary Hyperparathyroidism With Concurrent Primary Aldosteronism

Primary Hyperparathyroidism With Concurrent Primary Aldosteronism

Inactivation of the Carney Complex Gene 1 (Protein Kinase A Regulatory Subunit 1A) Inhibits SMAD3 Expression and TGFβ-Stimulated Apoptosis in Adrenocortical Cells

Hyperparathyroidism Can Be Useful in the Identification of Primary Aldosteronism Due To Aldosterone-Producing Adenoma

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