Figure 3.

Schematic diagram of potential mechanisms mediating GSI effects on Notch-related cancer radioresistance. In glioblastoma, NIC sustains: CSC survival via the anti-apoptotic protein MCL1 (induced myeloid leukemia cell differentiation protein) and BCL2 (B-cell lymphoma 2) as well as via the pro-survival pathway PI3K/AKT; angiogenesis via VEGF (vascular endothelial growth factor) signaling that transforms stromal cells (SC) to endothelial cells (EC), and selecting the perivascular niche (PVN) cells. On the other hand, Notch1 knockdown stimulates the formation of cell-communicating network (tCN) inside the tumor. In colon cancer, HES1 counteracts the accumulation of DNA damage by sustaining DNA-PK (DNA-dependent protein kinase) implicated in DNA repair following exposure to radiation (hν), therefore sustaining CSC survival. In breast cancer, the Notch target genes HES1 and HEY1 are implicated in contrasting DNA damage accumulation, while NIC also mediates the inhibition of oncosuppressor protein E-Cadherin and the increase in CSC survival via unspecified mechanisms following exposure to hν. Additionally, radiation stimulates the IL-6/JAK/STAT3 axis that upregulates DLL4, Jagged1, and Notch2 expression that promote EMT. In NSCLC, NIC sustains CSC survival via HES1, MAPK (mitogen-activated protein kinase), and BCL2 upregulation and is implicated in the functional angiogenesis. In addition, HIF is associated with DLL4-related Notch stimulation, and radiation stimulates the NRF2/Notch axis that enhances EMT. Finally, in NSCLC, the combined GSI-radiation therapy results in Numb-dependent downregulation of Notch. “??” represents other unknown mechanisms which may be involved in Notch-dependent CSC survival.