Targeting specific regions of the Notch3 ligand-binding domain induces apoptosis and inhibits tumor growth in lung cancer.
Like many signaling pathways in development, the Notch receptor pathway plays an important role in cancer pathobiology when it is dysregulated. Potential ligand-binding sites within the epidermal growth factor (EGF)-like repeats of Notch1 have been identified, but the ligand-binding domains in Notch3, which is implicated in lung cancer, are not known. In screening a library of 155 peptides representing all 34 EGF-like repeats in Notch3, we discovered two distinct ligand-binding regions involving the 7-10 and 21-22 repeats that are distinct from the putative ligand-binding domain of Notch1. In cell-based assays, peptides from these regions induced apoptosis and reduced expression of the Notch3-dependent gene Hey1. They also bound directly to the Notch ligand Jagged1, suggesting that their mechanism of action involves disrupting interactions between Notch3 and Jagged1. Recombinant Fc fusion peptides engineered for in vivo testing showed that the Notch3 peptides defined could trigger apoptosis and suppress tumor growth in tumor xenograft assays. These findings rationalize a mechanistic approach to lung cancer treatment based on Notch3 receptor-targeted therapeutic development.
Lin
Luping
L
Department of Cancer Biology, Division of Hematology and Medical Oncology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Mernaugh
Ray
R
Yi
Fuming
F
Blum
David
D
Carbone
David P
DP
Dang
Thao P
TP
D017209:Apoptosis / Q000187:drug effects*; D051792:Basic Helix-Loop-Helix Proteins / Q000096:biosynthesis / Q000235:genetics; D001665:Binding Sites; D002135:Calcium-Binding Proteins / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000096:biosynthesis / Q000235:genetics; D048708:Cell Growth Processes / Q000502:physiology; D016503:Drug Delivery Systems; D004815:Epidermal Growth Factor / Q000235:genetics / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000235:genetics / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D000072100:Jagged-1 Protein; D008024:Ligands; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008565:Membrane Proteins / Q000378:metabolism; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D019151:Peptide Library; D017434:Protein Structure, Tertiary; D000071656:Receptor, Notch3; D051880:Receptors, Notch / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D000072099:Serrate-Jagged Proteins
D051792:Basic Helix-Loop-Helix Proteins; D002135:Calcium-Binding Proteins; D018797:Cell Cycle Proteins; D004815:Epidermal Growth Factor; D007141:Immunoglobulin Fc Fragments; D036341:Intercellular Signaling Peptides and Proteins; D000072100:Jagged-1 Protein; D008024:Ligands; D008565:Membrane Proteins; D010446:Peptide Fragments; D019151:Peptide Library; D000071656:Receptor, Notch3; D051880:Receptors, Notch; D011993:Recombinant Fusion Proteins; D000072099:Serrate-Jagged Proteins; C485631:HEY1 protein, human; C000606273:JAG1 protein, human; C499374:NOTCH3 protein, human