Targeting Specific Regions of the Notch3 Ligand-Binding Domain Induces Apoptosis And Inhibits Tumor Growth In Lung Cancer

摘要

Like many signaling pathways in development, the Notch pathway also plays a role in cancers when it is dysregulated. Studies involving deletions of several epidermal growth factor (EGF)-like repeats in the extracellular domains of Drosophila Notch and mammalian Notch1 have identified potential ligand binding sites. However, the ligand binding domain in Notch3 is not known. Using a screening library of 155 peptides representing the entire 34 EGF-like repeats in Notch3, we discovered two distinct ligand binding regions involving the 7–10 and 21–22 repeats. They are also distinct from the putative ligand binding region of Notch1. The peptides from these regions induced apoptosis and reduced expression of the Notch3-dependent gene Hey1. They also bind directly to the ligand Jagged1, suggesting that the mechanism of activity involves the disruption of the interaction between Notch3 and Jagged1. Notch3 recombinant Fc-fusion proteins based on peptide sequences induced apoptosis and suppressed tumor growth in xenografts. The findings from this study provide a promising rationale and mechanistic basis for Notch3 receptor-targeted therapeutic development in the treatment of patients with lung cancer.