Figure 1.

Diagram of the Notch3 signaling pathway in ovarian CSC. (a) In Notch3-overexpressing ovarian CSC, Notch signaling is triggered by ligand binding to Notch3 receptor, which undergoes a two-step proteolytic cleavage by ADAM family proteases and γ-secretases, respectively. Subsequently, the Notch3 intracellular domain (NICD3) is released and translocates into the nucleus, where it binds to CSL and converts the transcriptional complex from a repressor to an activator of Notch3 target genes, known to be implicated in CSC maintenance, drug resistance and tumor recurrence. (b) Notch3 signaling inhibition by γ-secretase inhibitors (GSIs) or monoclonal antibodies against Notch3 blocks Notch3 target gene activation, resulting in the reduction of CSCs, increased chemosensitivity and tumor regression.