1. The Notch-  -Secretase Pathway

2. Notch activation involves the proteolytic cleavage of the Notch ligand/receptor complex by  -secretase to release the Notch intracellular domain fragment (NICD) that translocates to the nucleus and upregulates expression of Myc, Hes1, and other genes. 1 When the DAOY medulloblastoma cell line was transfected with NICD2 to make Notch signaling constitutively active, the transfected cells produced more xenograft tumors than the non-transformed DAOY cells and increased the population of both CD133 + and side population stem-like cells in culture. In contrast, inhibition of  -secretase reduced the side population to 0.01% of the total cell count and inhibited by 90% the ability of cells to colonize soft agar or to form tumor xenografts in immune-compromised mice. NICD2 transfection protected the cells from the effects of  - secretase inhibition. 2 Thus, in some tumor types, the inhibition of Notch signaling can deplete a population of cells that are required for tumor initiation.

3. References 1. O'Neil, J., et al., FBW7 mutations in leukemic cells mediate NOTCH pathway activation and resistance to  -secretase inhibitors. J. Exp. Med., 204, 1813-1824 (2007). 2. Fan, X., et al., Notch pathway inhibition depletes stem-like cells and blocks engraftment in embryonal brain tumors. Cancer Res., 66, 7445-7452 (2006).