Abstract
BackgroundProstate 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.MethodsPCSCs 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.ResultsPC-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.ConclusionsThese 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.
Highlights
Prostate cancer is the most common cancer in the USA, and it is estimated that there will be 191,930 newly diagnosed prostate cancer cases and 33,330 deaths due to prostate cancer in 2020 [1]
Notch-1 receptor expression is increased in PC-3 Prostate cancer stem-like cells (PCSCs) We cultured human PC-3 prostate cancer cells in growth factor defined serum-free medium for the enrichment of PCSCs and detected the stem cell markers including Notch-1, Oct-4, and Nanog in PCSCs and parental cells
We examined whether PCSCs have a differential response to DOX compared with parental cells
Summary
Prostate cancer is the most common cancer in the USA, and it is estimated that there will be 191,930 newly diagnosed prostate cancer cases and 33,330 deaths due to prostate cancer in 2020 [1]. Conventional therapies, such as radical prostatectomy, radiotherapy, and hormone therapy, are effective in the starting phase of prostate. Docetaxel (DOX) is frequently utilized as a firstline chemotherapy in metastatic and advanced prostate cancer, not all the patients respond to DOX, and in those. Targeting PCSCs and enhancing DOX activity would provide a major benefit to patients. Prostate cancer stem-like cells (PCSCs) likely participate in tumor progression and recurrence and demonstrate resistance to chemotherapy. This study aimed to investigate the efficacy of Notch signaling inhibition as an adjuvant to docetaxel (DOX) in PCSCs
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