Notch Antagonists: Potential Modulators of Cancer and Inflammatory Diseases

Abstract

Notch is a key player in various developmental processes during the embryonic stage as well as in regulating tissue homeostasis, cell differentiation, and stem cell maintenance in adult life. Activation of Notch signaling occurs following Notch receptor-ligand interaction and subsequent enzymatic proteolysis by the gamma-secretase complex, resulting in the cytoplasmic release of a Notch intracellular domain, which translocates to the nucleus to initiate the downstream transcriptional machinery. Notch activation and its aberrant signaling have been broadly linked to the pathogenesis of cancer and some chronic inflammatory diseases resulting in pathologic fibrotic processes. This review focuses on the molecular basis of Notch-induced signaling and its interaction with other pathways to identify therapeutic targets. We also highlight current efforts to pharmacologically intervene in Notch signaling and discuss promising ongoing experimental and clinical studies.

Hippo Cascade Controls Lineage Commitment of Liver Tumors in Mice and Humans

“…Specifically, anti-Notchespecific antibodies as well as small molecules targeting Notch, such as g-secretases inhibitors and staple peptides, have been tested in various human cancers. 68 It is possible that human HCC and ICCs with loss of Hippo cascade may benefit from anti-Notchebased therapy, and nuclear Yap/TAZ expression might represent a useful biomarker to stratify liver cancer patients for anti-Notch therapies.…”

Notch signaling pathway regulates cell cycle in proliferating hepatocytes involved in liver regeneration

“…In mammals, Notch system consists of four transmembrane receptors (Notch‐1, Notch‐2, Notch‐3, and Notch‐4) and five ligands belonging to the Jagged (Jagged‐1 and Jagged‐2) and Delta‐like (Dll‐1, Dll‐3, and Dll‐4) families . Ligand–receptor binding leads to the proteolytic cleavage processes in Notch receptor mediated by γ‐secretase complex and the release of Notch intracellular domain (NICD), resulting in transcription of Notch target genes, such as Hes and Hey . Recently, several clinical observations and basic studies have demonstrated that Notch signaling is involved in liver regeneration .…”

COX-2 regulates Snail expression in gastric cancer via the Notch1 signaling pathway

“…The Notch signalling pathway is a highly evolutionarily conserved signal transduction system (25). The Notch receptor transmits intracellular signals by interacting with ligands and plays important regulatory roles in cell proliferation, differentiation and apoptosis (26)(27)(28). Mammals possess four Notch receptors (Notch1-4), and Notch ligands include Jagged1, Jagged2, DLL1, DLL3 and DLL4 (29).…”