Neuromedin B receptor as a potential therapeutic target for corticotroph adenomas.

Cushing's disease (CD) results from autonomous adrenocorticotropic hormone (ACTH) secretion by corticotroph adenomas, leading to excessive cortisol production, ultimately affecting morbidity and mortality. Pasireotide is the only FDA approved tumor directed treatment for CD, but it is effective in only about 25% of patients, and is associated with a high rate of hyperglycemia. Neuromedin B (NMB), a member of the bombesin-like peptide family, regulates endocrine secretion and cell proliferation. Here, we assessed NMB and NMB receptor (NMBR) expression in human corticotroph adenomas and the effects of NMBR antagonist PD168368 on murine and human corticotroph tumors.To investigate NMB and NMBR expression, real-time qPCR and immunostaining on human pathological specimens of corticotroph, non-functional and somatotroph adenomas were performed. The effects of PD168368 on hormone secretion and cell proliferation were studied in vitro, in vivo and in seven patient-derived corticotroph adenoma cells. NMB and NMBR were expressed in higher extent in human corticotroph adenomas compared with non-functional or somatotroph adenomas.In murine AtT-20 cells, PD168368 reduced proopiomelanocortin (Pomc) mRNA/protein expression and ACTH secretion as well as cell proliferation. In mice with tumor xenografts, tumor growth, ACTH and corticosterone were downregulated by PD168368. In patient-derived adenoma cells, PD168368 reduced POMC mRNA expression in four out of seven cases and ACTH secretion in two out of five cases. A PD168368-mediated cyclin E suppression was also identified in AtT-20 and patient-derived cells.NMBR antagonist represents a potential treatment for CD and its effect may be mediated by cyclin E suppression.© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.

Citation

Tomonori Sekizaki, Hiraku Kameda, Akinobu Nakamura, Saki Kuwabara, Hiroshi Nomoto, Kyu Yong Cho, Yukitomo Ishi, Hiroaki Motegi, Hideaki Miyoshi, Tatsuya Atsumi. Neuromedin B receptor as a potential therapeutic target for corticotroph adenomas. Pituitary. 2023 Aug 29

PMID: 37642928

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