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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Oncol. | doi: 10.3389/fonc.2019.00809

DAPT, a γ-secretase inhibitor, suppresses tumorigenesis and progression of growth hormone-producing adenomas by targeting Notch signaling

 JIE FENG1, Jianpeng Wang1,  Qian Liu1, Jiye Li1,  Qi Zhang2, Zhengping Zhuang2, Xiaohui Yao3, Chunhui Liu1, Yangfang Li1, Lei Cao1,  CHUZHONG LI1, Lei Gong1, Dan Li1,  Yazhuo Zhang1 and Hua Gao1*
  • 1Beijing Neurosurgical Institute, Beijing Tiantan Hospital, Capital Medical University, China
  • 2National Institute of Neurological Disorders and Stroke (NINDS), United States
  • 3Shanxi Provincial People's Hospital, China

Advances in the understanding of growth hormone-producing adenomas (GHomas) are ongoing, but current therapy is limited by moderate and variable efficacy and in need of life-long treatment. In this study, the molecular signaling pathway related to GHoma was investigated by proteomics and transcriptomics. The differentially expressed proteins and genes were significantly enriched in Extracellular Matrix-Receptor Interactions, Notch Signaling, Basal Cell Carcinoma Signaling, JAK-STAT3, Wnt Signaling and Glioblastoma Multiforme Signaling by Ingenuity Pathway Analysis. Furthermore, the Notch2/Delta-like canonical Notch ligand (DLL) signaling pathway was identified to be associated with tumorigenesis and invasiveness of GHoma. In 76 patients, Notch2 and DLL3 were upregulated in invasive compared to those in non-invasive GHoma (p<0.05). Disease-free survival was significantly longer in patients with low, compared with high, DLL3 expression (p=0.027). Notch 2 knockdown inhibited cell migration in both GH3 cells and primary GHoma cells, along with downregulation of the mRNA expression of related genes. DAPT, a γ-secretase inhibitor, inhibited tumor growth and invasion in vivo and in vitro and suppressed the release of growth hormone in primary GHoma cells. The involvement of Notch2/DLL3 signaling in GHoma progression warrants additional study of Notch inhibitor, DAPT, as a potential GHoma treatment.

Keywords: pituitary adenoma, Growth hormone-producing adenomas, Notch signaling, inhibitor, DAPT, invasion

Received: 02 Nov 2018; Accepted: 07 Aug 2019.

Copyright: © 2019 FENG, Wang, Liu, Li, Zhang, Zhuang, Yao, Liu, Li, Cao, LI, Gong, Li, Zhang and Gao. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Hua Gao, Beijing Neurosurgical Institute, Beijing Tiantan Hospital, Capital Medical University, Beijing, China,