Inhibition of Notch pathway enhances the anti-tumor effect of docetaxel in prostate cancer stem-like cells

Abstract

Abstract Background Prostate cancer stem-like cells (PCSCs) likely participate in tumor progression and recurrence and demonstrate resistance to chemotherapy. The Notch pathway plays a role in the maintenance of the stemness in PCSCs. This study aimed to investigate the efficacy of Notch signaling inhibition as an adjuvant to docetaxel (DOX) in PCSCs. Methods PCSCs derived from the PC-3 cell line were examined for Notch-1 expression. The effect of Notch inhibition on response to DOX was evaluated in PCSCs in vitro and in murine models using a γ-secretase inhibitor (GSI), PF-03084014. Impacts on cell proliferation, apoptosis, cell cycle, and sphere formation were evaluated. Results PC-3 PCSCs expressed elevated Notch-1 mRNA compared with PC-3 parental cells. The combination of GSI with DOX promoted DOX-induced cell growth inhibition, apoptosis, cell cycle arrest, and sphere formation in PCSCs. In nude mice bearing PC-3 PCSC-derived tumors, the combination of GSI and DOX reduced the tumor growth, which was associated with the decreased Notch-1 expression in tumor tissues. Conclusions These results reveal that inhibition of the Notch pathway enhances the anti-tumor effect of DOX in PC-3 PCSCs, and suggest that Notch inhibition may have clinical benefits in targeting PCSCs.