NOTCH1 signaling promotes chemoresistance via regulating ABCC1 expression in prostate cancer stem cells

Abstract

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.

MicroRNA-34a Attenuates Paclitaxel Resistance in Prostate Cancer Cells via Direct Suppression of JAG1/Notch1 Axis

“…We performed a series of in vitro and in vivo studies to obtain evidence that the decreased expression of miR-34a significantly contributes to lung and liver metastasis and chemoresistance through the inhibition of apoptosis and the JAG1/Notch1 axis in PC. Accumulating evidence shows that the induction of apoptosis and activation of Notch1 signaling pathways dramatically suppresses tumor growth, metastasis, and chemoresistance, including in PC [21,35,36]. Our data clearly showed that the overexpression of miR-34a significantly enhanced paclitaxel-induced apoptosis and Notch1 signaling pathway inhibition and dramatically inhibited PC metastasis in vivo, which indicates that the restoration of miR-34a may be a useful strategy for the treatment of metastasis and chemoresistance, in PC patients.…”

“…We identified JAG1 and Notch1 as tentative targets of miR-34a (Fig. 4C and 5C) because previous studies have shown that the Notch1 signaling pathway correlates closely with PC progression, metastasis, and chemoresistance [21,22]. Furthermore, sequence alignment of the predicted miR-34a showed high conservation among different species.…”

Overexpression of Notch1 is associated with the progression of cervical cancer

“…The canonical Notch1 signaling pathway is believed to be a fundamental transduction pathway involved in directly transmitting signals from the cell surface to the nucleus (21). Notch1 has been demonstrated to have essential roles in the regulation of tumor growth, invasion, metastasis and angiogenesis (11,(22)(23)(24). Furthermore, the overexpression of Notch1 has been observed in numerous types of human cancer (25,26), and Notch signaling has been reported to have an oncogenic role in breast (27), colorectal (28), ovarian (29), pancreatic and prostate cancer (30), as well as leukemia and lymphoma (31).…”

The role of prostate tumor overexpressed 1 in cancer progression

“…In PC, its role in progression has been studied in vitro and in vivo with contradictory results [65–67]. We have shown that PTOV1 in metastatic prostate tumors is significantly overexpressed and represses the transcription of the downstream targets of Notch, the HES1 and HEY1 genes, by interacting with SMRT, RBP-Jκ, NCoR, HDAC1 and HDAC4 (Figure 3) [32].…”