Long-Term Inhibition of Notch in A-375 Melanoma Cells Enhances Tumor Growth Through the Enhancement of , and as Intermediate Genes in Wnt and Notch Pathways.

Notch suppression by gamma-secretase inhibitors is a valid approach against melanoma. However, most of studies have evaluated the short-term effect of DAPT on tumor cells or even cancer stem cells. In the present study, we surveyed the short-term and long-term effects of DAPT on the stem cell properties of A375 and NA8 as melanoma cell lines. The effects of DAPT were tested both and using xenograft models. In A375 with B-raf mutation, DAPT decreased the level of , and as downstream genes of the Notch pathway. This was accompanied by enhanced apoptosis after 24 h treatment, arrest in the GM phase, and impaired ability of colony and melanosphere formation at the short term. Moreover, tumor growth also reduced during 13 days of treatment. However, long-term treatment of DAPT promoted tumor growth in the xenograft model and enhanced the number and size of colonies and spheroids . The gene expression studies confirmed the up-regulation of Wnt and Notch downstream genes as well as , and following the removal of Notch inhibitor and in the xenograft model. Moreover, the Gompertz-based mathematical model determined a new drug resistance term in the present study. Our data supported that the long-term and not short-term inhibition of Notch by DAPT may enhance tumor growth and motility through up-regulation of , and genes in B-raf mutated A375 cells.