Primary Aldosteronism: Metabolic Reprogramming and the Pathogenesis of Aldosterone-Producing Adenomas

Gong, Siyuan; Tetti, Martina; Reincke, Martín; Williams, Tracy Ann

doi:10.3390/cancers13153716

Cited by 7 publications

(7 citation statements)

References 72 publications

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“…In a recent study, transcriptome data analysis identified alterations in transcriptome signatures in pathways related to mitochondrial fatty acid β-oxidation and peroxisome proliferator receptor-α ( PPARα ), with suppression of ferroptosis suppressor genes and overexpression of genes related to glycolysis/glyconeogenesis in APAs. Furthermore, KCNJ5 mutated APAs that have a higher proliferative index display increased expression of genes involved in glycolysis and lipid metabolism, an observation reminiscent of the well-characterized role of metabolic reprogramming in cancer progression [ 75 ].…”

Section: Resultsmentioning

confidence: 99%

“…On the contrary, adrenocortical tumor cells appeared to possess mechanisms for counteracting metabolic stress through upregulation of antioxidant systems. APAs were documented to display a high proportion of tumor cells, suggesting that their particular transcriptome profile enables them to escape from immune surveillance [ 75 ].…”

Section: Resultsmentioning

confidence: 99%

“…Several metabolic adaptations have since been described in tumorigenesis, with tumor cells undergoing metabolic reprogramming in order to address increased metabolic demands and enhance progression. Characteristic examples include increased glucolysis in cancer cells (the Warburg effect) and the dysregulation of lipid oxidation with increased β-oxidation and subsequent increased NADPH (also critical for adrenal steroidogenesis) with enhancement of CYP11A1 and CYP11B2 activity, possibly leading to increased aldosterone synthesis [ 75 ].…”

Section: Resultsmentioning

confidence: 99%

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Transcriptomics, Epigenetics, and Metabolomics of Primary Aldosteronism

Spyroglou

Piaditis

Kaltsas

et al. 2021

Cancers

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Introduction: Primary aldosteronism (PA) is the most common cause of endocrine hypertension, mainly caused by aldosterone-producing adenomas or hyperplasia; understanding its pathophysiological background is important in order to provide ameliorative treatment strategies. Over the past several years, significant progress has been documented in this field, in particular in the clarification of the genetic and molecular mechanisms responsible for the pathogenesis of aldosterone-producing adenomas (APAs). Methods: Systematic searches of the PubMed and Cochrane databases were performed for all human studies applying transcriptomic, epigenetic or metabolomic analyses to PA subjects. Studies involving serial analysis of gene expression and microarray, epigenetic studies with methylome analyses and micro-RNA expression profiles, and metabolomic studies focused on improving understanding of the regulation of autonomous aldosterone production in PA were all included. Results: In this review we summarize the main findings in this area and analyze the interplay between primary aldosteronism and several signaling pathways with differential regulation of the RNA and protein expression of several factors involved in, among others, steroidogenesis, calcium signaling, and nuclear, membrane and G-coupled protein receptors. Distinct transcriptomic and metabolomic patterns are also presented herein, depending on the mutational status of APAs. In particular, two partially opposite transcriptional and steroidogenic profiles appear to distinguish APAs carrying a KCNJ5 mutation from all other APAs, which carry different mutations. Conclusions: These findings can substantially contribute to the development of personalized treatment in patients with PA.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Transcriptomics, Epigenetics, and Metabolomics of Primary Aldosteronism

Spyroglou

Piaditis

Kaltsas

et al. 2021

Cancers

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“…Somatic mutations of KCNJ5, ATP1A1, ATP2B3, CACNA1D, CACNA1H, CLCN2, or CTNNB1 genes that drive autonomous aldosterone production have been documented in APAs [5][6][7][8][9][10][11][12][13]. Recently, Gong, et al, suggested that metabolic reprograming involved with tumorigenesis in KCNJ5 mutant APA [14]. However, the molecular mechanisms of genesis or growth of APAs mediated by ATP1A1 mutations have not been elucidated.…”

Section: Introductionmentioning

confidence: 99%

ATP1A1 Mutant in Aldosterone-Producing Adenoma Leads to Cell Proliferation

Kobuke

Oki

Gómez-Sánchez

et al. 2021

IJMS

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The molecular mechanisms by which ATP1A1 mutation-mediated cell proliferation or tumorigenesis in aldosterone-producing adenomas (APAs) have not been elucidated. First, we investigated whether the APA-associated ATP1A1 L104R mutation stimulated cell proliferation. Second, we aimed to clarify the molecular mechanisms by which the ATP1A1 mutation-mediated cell proliferated. We performed transcriptome analysis in APAs with ATP1A1 mutation. ATP1A1 L104R mutation were modulated in human adrenocortical carcinoma (HAC15) cells (ATP1A1-mutant cells), and we evaluated cell proliferation and molecular signaling events. Transcriptome and immunohistochemical analysis showed that Na/K-ATPase (NKA) expressions in ATP1A1 mutated APA were more abundant than those in non-functioning adrenocortical adenoma or KCNJ5 mutated APAs. The significant increase of number of cells, amount of DNA and S-phase population were shown in ATP1A1-mutant cells. Fluo-4 in ATP1A1-mutant cells were significantly increased. Low concentration of ouabain stimulated cell proliferation in ATP1A1-mutant cells. ATP1A1-mutant cells induced Src phosphorylation, and low concentration of ouabain supplementation showed further Src phosphorylation. We demonstrated that NKAs were highly expressed in ATP1A1 mutant APA, and the mutant stimulated cell proliferation and Src phosphorylation in ATP1A1-mutant cells. NKA stimulations would be a risk factor for the progression and development to an ATP1A1 mutant APA.

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“…The molecular features of a novel mutation in the ATP2B3 gene are presented in detail in the article by Liao et al [ 2 ]. By using advanced bioinformatics approaches, Gong et al characterized the metabolome and tissue microenvironment in aldosterone-producing adenomas and showed metabolic reprogramming toward fatty acid β-oxidation and glycolysis; moreover, an immunosuppressive tissue microenvironment was also found [ 3 ]. In a systematic review, Spyroglou et al present recent developments in the transcriptomics, epigenetics and metabolomics of primary aldosteronism [ 4 ].…”

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confidence: 99%