AUTHOR=Feng Jie , Wang Jianpeng , Liu Qian , Li Jiye , Zhang Qi , Zhuang Zhengping , Yao Xiaohui , Liu Chunhui , Li Yangfang , Cao Lei , Li Chuzhong , Gong Lei , Li Dan , Zhang Yazhuo , Gao Hua 

TITLE=DAPT, a γ-Secretase Inhibitor, Suppresses Tumorigenesis, and Progression of Growth Hormone-Producing Adenomas by Targeting Notch Signaling

JOURNAL=Frontiers in Oncology

VOLUME=9

YEAR=2019

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2019.00809

DOI=10.3389/fonc.2019.00809

ISSN=2234-943X

ABSTRACT=<p>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 (<italic>p</italic> &lt; 0.05). Disease-free survival was significantly longer in patients with low, compared with high, DLL3 expression (<italic>p</italic> = 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 <italic>in vivo</italic> and <italic>in vitro</italic> 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.</p><sec id="s1"><title>Importance of the Study</title><p>Current treatments of GH adenomas (GHomas) are limited by their moderate and variable efficacy and in need of life-long treatment. We found that the Notch2/Delta-like Notch ligand 3 (DLL3) signaling pathway was active in GHoma tumorigenesis, progression, and invasion.</p><p>The γ-secretase inhibitor DAPT is of potential use in GHoma treatment targeting Notch signaling.</p></sec>