title: Prostate cancer stem-like cells proliferate slowly and resist etoposide-induced cytotoxicity via enhancing DNA damage response.
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.
authors.affiliation: 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.
authors.forename: Judy
authors.initials: J
authors.lastname: Yan
authors.affiliation: 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.
authors.forename: Damu
authors.initials: D
authors.lastname: Tang
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects*; D003114:Colony-Forming Units Assay; D004249:DNA Damage / Q000187:drug effects* / Q000235:genetics; D005047:Etoposide / Q000494:pharmacology*; D005455:Fluorescent Antibody Technique; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000473:pathology*; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D014407:Tumor Cells, Cultured
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D005047:Etoposide
keywords: Cell proliferation; Cell signaling; DNA damage response; Prostate cancer stem cell; Tumorigenesis