Cover Picture: Canonical Notch signaling pathway and potential sites of inhibition. The Notch pathway is primed through cell-to-cell interaction distinguishing it from other regulatory pathways. Following ligand secretion from a transmitting cell, the ligand binds to one of the four Notch receptors on the receiver cell. Ligand-receptor binding facilitates the cleavage of the intracellular component of the transmembrane receptor via γ-secretase. Successful cleavage activates the Notch intracellular component domain (NICD) which translocates to the nucleus where is regulated a host of transcription factors. Given the intricacy of the pathway, there are multiple key regulatory steps poised for targeted therapy. First, monoclonal antibody and decoy administration at both the Notch ligand and receptor is in preliminary, preclinical investigation. Second, γ-secretase inhibitors are the most studied target within the pathway; however, there is limited data within hepatocellular carcinoma. Finally, inactivating transcriptional peptides are a novel trend focused on inhibiting the canonical transcription mediated by NICD.
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