Down-regulation of Notch-1 by γ-secretase inhibitor suppress the proliferation and migration of prostate cancer cells

Abstract

Notch-1 signaling is crucial for stem cell maintenance and in a variety of tissues. Previous research has demonstrated that Notch-1 activity plays a key role in prostate tumorigenesis. However, the function of Notch-1 signaling in tumorigenesis can be either oncogene or suppressor gene. In our paper, γ- secretase inhibitor (N-[N-(3,5-difluorophenacetyl) -L-alanyl] -S-phenylglycine t-butyl ester, (DAPT) was used to block the release of Notch-1 intracellular domain (NICD). We investigated whether DAPT plays a role in the regulation of the proliferation and migration of prostate cancer cells through down-regulation of the Notch-1 activation. Here, we reported that DAPT treatment inhibited the PC cells proliferation and migration in dose- and time- dependent manner. The expression of Notch-1 was decreased significantly. MT1-MMP and its target-molecule MMP2, which function in cell migration-related behavior, also decreased in accordance with NICD. DAPT treatment for 24 h also down-regulated the binding between NICD and hes-1 promoter by chromatin immunoprecipitation assay (ChIP). Taken together, we demonstrate that DAPT inhibited the proliferation and migration of PC cells through down-regulation of the Notch-1 activation and its targeted genes.

Key words: Prostate cancer, γ-secretase activation, Notch signaling, MT1-MMP.