Chemotherapy is a strategy
for patients with advanced prostate cancer, especially those with castration-resistant prostate cancer. Prostate cancer stem cells (PCSCs) are believed to be the origin of cancer recurrence following therapy intervention, including chemotherapy. The mechanisms underlying the chemoresistance of PCSCs are still poorly understood. In the present study, fluorescence-activated cell sorting was used to isolate PCSCs from LNCaP and PC3 cell lines. 3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide was used to measure the cell viability. Quantitative real-time PCR and western blotting were utilized to evaluate the mRNA and protein levels. ShRNA was employed to knock down target gene expression. Chromatin immunoprecipitation (ChIP) was performed to explore the detailed mechanism underlying ABCC1 expression. Our results revealed that the sorted PCSCs showed enhanced chemoresistance ability than matched non-PCSCs. Protein level of activated form of NOTCH1(ICN1) was significantly higher in PCSCs. Inhibition of NOTCH1 with shRNA could decrease ABCC1 expression, and improve chemosensitivity in PCSCs. Finally, ChIP–PCR showed ICN1 could directly bind to the promoter region of ABCC1. In conclusion, NOTCH1 signaling could transactivate ABCC1, resulting in higher chemoresistance ability of PCSCs, which might be one of the important mechanisms underlying the chemoresistance of PCSCs.
Prostate cancer stem cells Chemoresistance NOTCH1 ABCC1
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This work was supported by the National Natural Science Foundation of China (Nos. 81001138, 81101519); Natural Science Foundation of Guangdong Province (Nos. 06021283, 10151008901000024, 10151008901000070, S2011040003777); Science and Technology Development Program of Guangdong Province (Nos. 2008B030301078, 2012B031800081); Young Teacher Foundation of Sun Yat-Sen University (Nos. 11ykpy33, 12ykpy31); and Yat-Sen Scholarship for Young Scientists (B L). Liu Cheng received Grant 163 from Key Laboratory of Malignant Tumor Molecular Mechanism and Translational Medicine of Guangzhou Bureau of Science and Information Technology.
Conflict of interest
The authors declare no conflict of interest.
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