Abstract
We recently demonstrated that the orphan nuclear receptor testicular receptor 4 (TR4) is a potent regulator of corticotroph tumor growth and hormone secretion. The Ras/Raf/MEK/ERK pathway is commonly overactivated in human tumors and we have demonstrated that corticotroph tumor TR4 is activated by ERK1/2-mediated phosphorylation. We evaluated effects of MEK-162, a selective, non-ATP-competitive allosteric inhibitor of MEK1/2, on murine and human in vitro and in vivo corticotroph tumor proliferation and adrenocorticotrophic hormone (ACTH) secretion. MEK-162 treatment dose-dependently inhibited corticotroph tumor proliferation, induced apoptosis, reduced pro-opiomelanocortin (POMC) mRNA levels and inhibited ACTH secretion in vitro. Similar findings were obtained in human corticotroph tumor primary cultures (n = 5). These actions of MEK-162 were augmented in the presence of TR4 overexpression, suggesting that TR4 levels may serve as a predictive biomarker of MEK-162 corticotroph tumor responsiveness. Additionally, MEK-162 treatment reduced TR4 protein expression and blocked recruitment of TR4 to bind its consensus site on the POMC promoter (−854bp to −637bp), elucidating multiple mechanisms to control TR4 corticotroph tumor actions. In a murine corticotroph tumor in vivo model of Cushing's disease, MEK-162 treatment inhibited tumor growth and reduced tumor-derived circulating plasma ACTH, and corticosterone levels. These results demonstrate the potent actions of MEK-162 to inhibit corticotroph tumor growth and hormone secretion in vitro and in vivo via TR4-dependent and independent mechanisms, and raise the possibility of MEK-162 as a novel therapy for Cushing's disease.
Highlights
Pituitary adenomas are commonly encountered intracranial tumors and cause significant morbidity and mortality due to local compressive effects and hormonal hypersecretion [1]
Cushing disease is a life-threatening neuroendocrine disorder caused by a pituitary adenoma, which leads to excess adrenocorticotrophic hormone (ACTH) secretion, and adrenal-derived cortisol
The specific targets of Ras/Raf/MEK/ERK pathway in the pathogenesis of pituitary adenomas are largely uncharacterized, our recent findings show that testicular receptor 4 (TR4), a potent regulator of corticotroph tumor growth and hormone secretion, is activated by ERK-mediated phosphorylation to regulate hormone synthesis [9]
Summary
Pituitary adenomas are commonly encountered intracranial tumors and cause significant morbidity and mortality due to local compressive effects and hormonal hypersecretion [1]. In particular Cushing’s disease, due to an adrenocorticotrophic hormone (ACTH)-secreting pituitary adenoma, results in excessive adrenal cortisol secretion, leading to increased morbidity and mortality [2,3,4,5]. Transphenoidal resection is currently first-line therapy offering initial remission rates of 70-80% in expert centers for microadenomas [1]. Available drugs for Cushing’s disease treatment include the dopamine D2 receptor agonist, cabergoline and the somatostatin receptor ligand pasireotide that inhibit tumor-derived ACTH secretion; steroidogenesis inhibitors such as ketoconazole and metyrapone; and the glucocorticoid receptor antagonist mifepristone [1, 6]. Safe and efficacious therapies that act directly www.impactjournals.com/oncotarget on the tumor to control both hormonal hypersecretion and pituitary corticotroph tumor growth are needed
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