A Novel Positive Feedback Loop Between NTSR1 and Wnt/β-Catenin Contributes to Tumor Growth of Glioblastoma

Abstract

Background/Aims: Neurotensin (NTS), an intestinal hormone, is profoundly implicated in cancer progression through binding its primary receptor NTSR1. The conserved Wnt/β-Catenin pathway regulates cell proliferation and differentiation via activation of the β-catenin/T-cell factor (TCF) complex and subsequent modulation of a set of target genes. In this study, we aimed to uncover the potential connection between NTS/NTSR1 signaling and Wnt/β-Catenin pathway. Methods: Genetic silencing, pharmacological inhibition and gain-of-function studies as well as bioinformatic analysis were performed to uncover the link between NTS/ NTSR1 signaling and Wnt/β-Catenin pathway. Two inhibitors were used in vivo to evaluate the efficiency of targeting NTS/NTSR1 signaling or Wnt/β-Catenin pathway. Results: We found that NTS/NTSR1 induced the activation of mitogen-activated protein kinase (MAPK) and the NF-κB pathway, which further promoted the expression of Wnt proteins, including Wnt1, Wnt3a and Wnt5a. Meanwhile, the mRNA and protein expression levels of NTSR1 were increased by the Wnt pathway activator Wnt3a and decreased by the Wnt inhibitor iCRT3 in glioblastoma cells. Furthermore, pharmacological inhibition of NTS/NTSR1 or Wnt/β-Catenin signaling suppressed tumor growth in vitro and in vivo. Conclusion: These results reveal a positive feedback loop between NTS/NTSR1 and Wnt/β-Catenin signaling in glioblastoma cells that might be important for tumor development and provide potential therapeutic targets for glioblastoma.

Absence of neurotensin attenuates intestinal dysbiosis and inflammation by maintaining Mmp7/α‐defensin axis in diet‐induced obese mice

“…NT has been shown to activate NF‐κB signaling pathways 97 ; however, we show that NT negatively regulates α‐defensin gene expression and NF‐κB signaling in Paneth cells in the current study. In order to better understand the contradiction of our results with previous reports, we found that PKCτ negatively regulates NF‐κB signaling.…”

Increased expression of neurotensin in high grade serous ovarian carcinoma with evidence of serous tubal intraepithelial carcinoma

“…The unexpected observation during experimentation of NTSR1 knockdown being associated with a more epithelial phenotype while knockdown of NTSR3 resembled a more mesenchymal phenotype, is unique. Indeed, similar plasticity regarding epithelial and mesenchymal states in OvCa cells has been reported and a role for NTS signaling, primarily acting through the NTSR1 receptor, in EMT has been described in several cancers . Thus, because epithelial cells are more proliferative and exhibit greater collective cell migration, it is possible that the effects of NTSR1 knockdown reflect the shift in EMT state.…”

Promotion of β-Catenin/Forkhead Box Protein O Signaling Mediates Epithelial Repair in Kidney Injury

“…Dose and duration were selected according to previously published studies. 20 , 21 , 22 , 23 After 21 days, the animals were sacrificed, and kidneys were collected for the assessment of kidney fibrosis.…”