Taming the Notch Transcriptional Regulator for Cancer Therapy

Abstract

Notch signaling is a highly conserved pathway in all metazoans, which is deeply involved in the regulation of cell fate and differentiation, proliferation and migration during development. Research in the last decades has shown that the various components of the Notch signaling cascade are either upregulated or activated in human cancers. Therefore, its downregulation stands as a promising and powerful strategy for cancer therapy. Here, we discuss the recent advances in the development of small molecule inhibitors, blocking antibodies and oligonucleotides that hinder Notch activity, and their outcome in clinical trials. Although Notch was initially identified as an oncogene, later studies showed that it can also act as a tumor suppressor in certain contexts. Further complexity is added by the existence of numerous Notch family members, which exert different activities and can be differentially targeted by inhibitors, potentially accounting for contradictory data on their therapeutic efficacy. Notably, recent evidence supports the rationale for combinatorial treatments including Notch inhibitors, which appear to be more effective than single agents in fighting cancer.

High-throughput screening discovers antifibrotic properties of haloperidol by hindering myofibroblast activation

“…Is the ER stress also mediating the observed downregulation of Notch1 levels in response to haloperidol? Although the definitive answer to this question still needs to be provided, our data support the emerging view that ER stress might indeed control the Notch pathway, which is implicated in multiple processes during both development and disease (73). We observed that fibroblast treatment with haloperidol resulted in the upregulation of various ER stress markers, including Atf3, Fkbp11, and Gadd34, similarly to the potent ER stress inducers thapsigargin and tunicamycin.…”

Nrf2 promotes breast cancer cell migration via up‐regulation of G6PD/HIF‐1α/Notch1 axis

“…20 In order to explore the influence of Nrf2 on Notch pathway in breast cancer cells, the expression of ligand Figure 4A,B). 20 In order to explore the influence of Nrf2 on Notch pathway in breast cancer cells, the expression of ligand Figure 4A,B).…”

“…The main functions of Notch pathway are regulating cells proliferation and migration. 20 In order to explore the influence of Nrf2 on Notch pathway in breast cancer cells, the expression of ligand Figure 4A,B). The expressions of Notch2-4, Dll1, Dll3, Dll4 and Jagged 1-2 were not affected by Nrf2 overexpression or Nrf2 knockdown in MCF-7 and MDA-MB-231 cells (Figure 4A,B).…”

Long non-coding RNAs in esophageal cancer: molecular mechanisms, functions, and potential applications

“…The EMT is also induced by several signaling pathways, such as the TGF-β and Notch signaling pathways [ 107 – 109 ]. The Notch signaling pathway is important for the development and progression of some tumors [ 110 , 111 ]. The lncRNA SNHG1 was shown to be overexpressed in ESCC tissues and correlated with lymph node metastasis, depth of invasion, and shorter OS time in ESCC patients [ 112 ].…”