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Neuromedin B receptor as a potential therapeutic target for corticotroph adenomas

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Abstract

Purpose

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.

Methods

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.

Results

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.

Conclusion

NMBR antagonist represents a potential treatment for CD and its effect may be mediated by cyclin E suppression.

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Data Availability

Some or all datasets generated during and/or analyzed during the current study are not publicly available but are available from the corresponding author on reasonable request.

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Acknowledgements

This work was supported by JSPS KAKENHI Grant Numbers 18H06229, 19K21329 and 20K17481, and the Akiyama Life Science Foundation. We thank Department of Surgical Pathology, Hokkaido University Hospital for cooperation in the preparation of archival pathological specimens. We thank Mark Cleasby, PhD from Edanz (https://jp.edanz.com/ac) for editing a draft of this manuscript.

Funding

This work was supported by JSPS KAKENHI Grant Numbers 18H06229, 19K21329 and 20K17481, and the Akiyama Life Science Foundation.

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Authors and Affiliations

  1. Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine, Graduate School of Medicine, Hokkaido University, N-15, W-7, Kita-ku, Sapporo, 060-8638, Japan

    Tomonori Sekizaki, Hiraku Kameda, Akinobu Nakamura, Saki Kuwabara, Hiroshi Nomoto, Kyu Yong Cho, Hideaki Miyoshi & Tatsuya Atsumi

  2. Clinical Research and Medical Innovation Center, Hokkaido University Hospital, Sapporo, Japan

    Kyu Yong Cho

  3. Department of Neurosurgery, Graduate School of Medicine, Hokkaido University, Sapporo, Japan

    Yukitomo Ishi & Hiroaki Motegi

Authors
  1. Tomonori Sekizaki
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  2. Hiraku Kameda
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  3. Akinobu Nakamura
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  5. Hiroshi Nomoto
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  6. Kyu Yong Cho
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  7. Yukitomo Ishi
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  8. Hiroaki Motegi
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  9. Hideaki Miyoshi
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  10. Tatsuya Atsumi
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Contributions

Tomonori Sekizaki and Hiraku Kameda designed the study, performed experiments and acquired the data. Tomonori Sekizaki and Hiroaki Motegi obtained clinical samples. Tomonori Sekizaki and Hiraku Kameda drafted the manuscript, and all other authors reviewed and revised the manuscript.

Corresponding author

Correspondence to Hiraku Kameda.

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The study was approved by the Institutional Review Board (No. 018–0201). All patients agreed to participate in the study and provided written informed consent.

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The authors declare no potential conflicts of interest.

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Sekizaki, T., Kameda, H., Nakamura, A. et al. Neuromedin B receptor as a potential therapeutic target for corticotroph adenomas. Pituitary 26, 597–610 (2023). https://doi.org/10.1007/s11102-023-01350-3

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