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Exp Cell Res. 2014 Oct 15;328(1):132-42. doi: 10.1016/j.yexcr.2014.08.016. Epub 2014 Aug 20.

Prostate cancer stem-like cells proliferate slowly and resist etoposide-induced cytotoxicity via enhancing DNA damage response.

Author information

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; Father Sean O׳Sullivan Research Institute, Hamilton, Ontario, Canada L8N 4A6; The Hamilton Centre for Kidney Research (HCKR), St. Joseph׳s Hamilton Healthcare, Hamilton, Ontario, Canada L8N 4A6.
2
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; Father Sean O׳Sullivan Research Institute, Hamilton, Ontario, Canada L8N 4A6; The Hamilton Centre for Kidney Research (HCKR), St. Joseph׳s Hamilton Healthcare, Hamilton, Ontario, Canada L8N 4A6. Electronic address: damut@mcmaster.ca.

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.

KEYWORDS:

Cell proliferation; Cell signaling; DNA damage response; Prostate cancer stem cell; Tumorigenesis

PMID:
25149681
DOI:
10.1016/j.yexcr.2014.08.016
[Indexed for MEDLINE]

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