Metformin suppresses growth and adrenocorticotrophic hormone secretion in mouse pituitary corticotroph tumor AtT20 cells

Jin, Kai; Ruan, Lunliang; Pu, Jiujun; Zhong, Ailing; Wang, Fuchao; Tan, Song; Huang, Hua; Mu, Jiamin; Ye, Gang

doi:10.1016/j.mce.2018.07.007

Cited by 17 publications

(13 citation statements)

References 26 publications

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“…At present, there are no clinical data available describing the role of metformin in the regulation of hormone production by functional PitNETs. However, in the abovementioned in vitro studies, metformin suppressed the production of ACTH and GH in pituitary tumor cell line models , Jin et al 2018. On the contrary, metformin treatment did not affect hormone secretion in primary cells derived from either ACTH-secreting, GH-secreting or prolactin-secreting PitNETs (Vázquez-Borrego et al 2019).…”

Section: The Role Of Metformin In Hormone Production By Pitnetsmentioning

confidence: 99%

“…Currently, there are limited studies suggesting the growth inhibitory effects of metformin on PitNETs. The antiproliferative effects of metformin have been seen on an ACTH-secreting mouse corticotroph tumor cell line, AtT20, and growth hormone-secreting PitNET cell lines GH3 and GH1 , Faggi et al 2018, Jin et al 2018. Besides growth inhibition, metformin-induced apoptosis in the cells by upregulating the expression of pro-apoptotic genes and downregulating the expression of anti-apoptotic genes.…”

Section: Preclinical Evidencementioning

confidence: 99%

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The role of an anti-diabetic drug metformin in the treatment of endocrine tumors

Thakur

Daley

Kłubo-Gwieździńska

2019

Journal of Molecular Endocrinology

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Incidence of endocrine cancers is rising every year. Over the last decade, evidence has accumulated that demonstrates the anti-cancer effects of an anti-diabetic drug, metformin, in endocrine malignancies. We performed a literature review utilizing the PubMed, Medline and clinicaltrials.gov databases using the keyword ‘metformin’ plus the following terms: ‘thyroid cancer’, ‘thyroid nodules’, ‘parathyroid’, ‘hyperparathyroidism’, ‘adrenal adenoma’, ‘Cushing syndrome’, ‘hyperaldosteronism’, ‘adrenocortical cancer’, ‘neuroendocrine tumor (NET)’, ‘pancreatic NET (pNET)’, ‘carcinoid’, ‘pituitary adenoma’, ‘pituitary neuroendocrine tumor (PitNET)’, ‘prolactinoma’, ‘pheochromocytoma/paraganglioma’. We found 37 studies describing the preclinical and clinical role of metformin in endocrine tumors. The available epidemiological data show an association between exposure of metformin and lower incidence of thyroid cancer and pNETs in diabetic patients. Metformin treatment has been associated with better response to cancer therapy in thyroid cancer and pNETs. Preclinical evidence suggests that the primary direct mechanisms of metformin action include inhibition of mitochondrial oxidative phosphorylation via inhibition of both mitochondrial complex I and mitochondrial glycerophosphate dehydrogenase, leading to metabolic stress. Decreased ATP production leads to an activation of a cellular energy sensor, AMPK, and subsequent downregulation of mTOR signaling pathway, which is associated with decreased cellular proliferation. We also describe several AMPK-independent mechanisms of metformin action, as well as the indirect mechanisms targeting insulin resistance. Overall, repositioning of metformin has emerged as a promising strategy for adjuvant therapy of endocrine tumors. The mechanisms of synergy between metformin and other anti-cancer agents need to be elucidated further to guide well-designed prospective trials on combination therapies in endocrine malignancies.

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Section: The Role Of Metformin In Hormone Production By Pitnetsmentioning

confidence: 99%

Section: Preclinical Evidencementioning

confidence: 99%

The role of an anti-diabetic drug metformin in the treatment of endocrine tumors

Thakur

Daley

Kłubo-Gwieździńska

2019

Journal of Molecular Endocrinology

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“…AMPK pathway is suggested to be a key mediator of glucocorticoid-metformin interaction (5,(34)(35)(36). In addition, metformin could show positive and protective effects during endogenous GC excess via an increase of serum insulin-like growth factor-I (37) and fibroblast growth factor 21 (38)(39)(40), and/or via a suppression of neuroendocrine tumor growth (9,41,42). However, the underlying mechanism behind a potential protection against glucocorticoid-associated adverse side-effects remains largely unknown.…”

Section: Discussionmentioning

confidence: 99%

Metformin and Bone Metabolism in Endogenous Glucocorticoid Excess: An Exploratory Study

et al. 2021

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ContextGlucocorticoid excess exhibits multiple detrimental effects by its catabolic properties. Metformin was recently suggested to protect from adverse metabolic side-effects of glucocorticoid treatment. Whether metformin is beneficial in patients with endogenous glucocorticoid excess has not been clarified.ObjectiveTo evaluate the phenotype in patients with endogenous Cushing’s syndrome (CS) treated with metformin at the time of diagnosis.Patients and MethodsAs part of the German Cushing’s Registry we selected from our prospective cohort of 96 patients all 10 patients who had been on pre-existing metformin treatment at time of diagnosis (CS-MET). These 10 patients were matched for age, sex and BMI with 16 patients without metformin treatment (CS-NOMET). All patients had florid CS at time of diagnosis. We analyzed body composition, metabolic parameters, bone mineral density and bone remodeling markers, muscle function and quality of life.ResultsAs expected, diabetes was more prevalent in the CS-MET group, and HbA1c was higher. In terms of comorbidities and the degree of hypercortisolism, the two groups were comparable. We did not observe differences in terms of muscle function or body composition. In contrast, bone mineral density in metformin-treated patients was superior to the CS-NOMET group at time of diagnosis (median T-Score -0.8 versus -1.4, p = 0.030). CS-MET patients showed decreased β-CTX levels at baseline (p = 0.041), suggesting reduced bone resorption under metformin treatment during glucocorticoid excess.ConclusionThis retrospective cohort study supports potential protective effects of metformin in patients with endogenous glucocorticoid excess, in particular on bone metabolism.

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“…Moreover, metformin tended to suppress the release of GH and ACTH from GH3 cells and AtT20 cells, respectively (91,97). As to the underlying cell signalling pathways, metformin activated AMPK in both AtT20 cells and GH3 cells (27,97). In AtT20 cells, the drug inhibited the IGF-1R/ AKT/mTOR pathway.…”

Section: Figurementioning

confidence: 99%

“…Metformin decreased cell proliferation and cell viability in AtT20 cells (ACTH-secreting mouse corticotroph cell line) (97), GH3-and GH1 cells (GH/PRLsecreting and GH-secreting cells, respectively) (27,91). Moreover, metformin tended to suppress the release of GH and ACTH from GH3 cells and AtT20 cells, respectively (91,97). As to the underlying cell signalling pathways, metformin activated AMPK in both AtT20 cells and GH3 cells (27,97).…”

Section: Figurementioning

confidence: 99%

How treatments with endocrine and metabolic drugs influence pituitary cell function

Tulipano

2020

Endocrine Connections

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A variety of endocrine and metabolic signals regulate pituitary cell function acting through the hypothalamus-pituitary neuroendocrine axes or directly at the pituitary level. The underlying intracellular transduction mechanisms in pituitary cells are still debated. AMP-activated protein kinase (AMPK) functions as a cellular sensor of low energy stores in all mammalian cells and promotes adaptive changes in response to calorie restriction. It is also regarded as a target for therapy of proliferative disorders. Various hormones and drugs can promote tissue-specific activation or inhibition of AMPK by enhancing or inhibiting AMPK phosphorylation, respectively. This review explores the preclinical studies published in the last decade that investigate the role of AMP-activated protein kinase in the intracellular transduction pathways downstream of endocrine and metabolic signals or drugs affecting pituitary cell function, and its role as a target for drug therapy of pituitary proliferative disorders. The effects of the hypoglycemic agent metformin, which is an indirect AMPK activator, are discussed. The multiple effects of metformin on cell metabolism and cell signalling and ultimately on cell function may be either dependent or independent of AMPK. The in vitro effects of metformin may also help highlighting differences in metabolic requirements between pituitary adenomatous cells and normal cells.

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Metformin suppresses growth and adrenocorticotrophic hormone secretion in mouse pituitary corticotroph tumor AtT20 cells

Cited by 17 publications

References 26 publications

The role of an anti-diabetic drug metformin in the treatment of endocrine tumors

The role of an anti-diabetic drug metformin in the treatment of endocrine tumors

Metformin and Bone Metabolism in Endogenous Glucocorticoid Excess: An Exploratory Study

How treatments with endocrine and metabolic drugs influence pituitary cell function

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Metformin suppresses growth and adrenocorticotrophic hormone secretion in mouse pituitary corticotroph tumor AtT20 cells

Cited by 17 publications

References 26 publications

The role of an anti-diabetic drug metformin in the treatment of endocrine tumors

The role of an anti-diabetic drug metformin in the treatment of endocrine tumors

Metformin and Bone Metabolism in Endogenous Glucocorticoid Excess: An Exploratory Study

How treatments with endocrine and metabolic drugs influence pituitary cell function

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Metformin suppresses growth and adrenocorticotrophic hormone secretion in mouse pituitary corticotroph tumor AtT20 cells