Prostate cancer stem-like cells proliferate slowly and resist etoposide-induced cytotoxicity via enhancing DNA damage response |
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Authors: | Judy Yan Damu Tang |
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Affiliation: | 1. Division of Nephrology, Department of Medicine, McMaster University, Juravinski Innovation Tower, Room T3310, St. Joseph?s Hospital, 50 Charlton Ave East, Hamilton, Ontario, Canada L8S 4L8;2. Father Sean O?Sullivan Research Institute, Hamilton, Ontario, Canada L8N 4A6;3. The Hamilton Centre for Kidney Research (HCKR), St. Joseph?s Hamilton Healthcare, Hamilton, Ontario, Canada L8N 4A6 |
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Abstract: | Despite the development of chemoresistance as a major concern in prostate cancer therapy, the underlying mechanisms remain elusive. In this report, we demonstrate that DU145-derived prostate cancer stem cells (PCSCs) progress slowly with more cells accumulating in the G1 phase in comparison to DU145 non-PCSCs. Consistent with the important role of the AKT pathway in promoting G1 progression, DU145 PCSCs were less sensitive to growth factor-induced activation of AKT in comparison to non-PCSCs. In response to etoposide (one of the most commonly used chemotherapeutic drugs), DU145 PCSCs survived significantly better than non-PCSCs. In addition to etoposide, PCSCs demonstrated increased resistance to docetaxel, a taxane drug that is commonly used to treat castration-resistant prostate cancer. Etoposide produced elevated levels of γH2AX and triggered a robust G2/M arrest along with a coordinated reduction of the G1 population in PCSCs compared to non-PCSCs, suggesting that elevated γH2AX plays a role in the resistance of PCSCs to etoposide-induced cytotoxicity. We have generated xenograft tumors from DU145 PCSCs and non-PCSCs. Consistent with the knowledge that PCSCs produce xenograft tumors with more advanced features, we were able to demonstrate that PCSC-derived xenograft tumors displayed higher levels of γH2AX and p-CHK1 compared to non-PCSC-produced xenograft tumors. Collectively, our research suggests that the elevation of DNA damage response contributes to PCSC-associated resistance to genotoxic reagents. |
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Keywords: | Prostate cancer stem cell Cell proliferation Cell signaling DNA damage response Tumorigenesis |
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