Daxx shortens mitotic arrest caused by paclitaxel.
Resistance to the anti-neoplastic drug paclitaxel is frequent in breast cancer patients. Most studies of paclitaxel resistance have focused on pathways that elicit cellular response, while little is known about players involved in the acquirement of taxane resistance. By screening a cohort of breast cancer cell lines, we observed a correlation between level of protein Daxx and response to paclitaxel. Cells lines expressing increased level of Daxx displayed a robust paclitaxel response with nearly all cells undergoing micronucleation, while cell lines with low amount of Daxx showed a decrease in micronucleation, and accumulation in mitosis. At used paclitaxel concentrations, apoptotic levels were negligible in all cell lines tested. Human cell lines expressing anti-Daxx siRNA as well as Daxx-/- mouse fibroblasts showed similar cellular response to paclitaxel. Importantly, absence or depletion of Daxx resulted in cell survival after paclitaxel treatment, as measured by colony formation assay. We conclude that Daxx may be an important predictive factor in cellular response to paclitaxel, which emphasizes a critical but unknown function of this protein in mitotic progression, which, when disabled, leads to survival advantages upon paclitaxel treatment.
Lindsay
Cory R
CR
Department of Anatomy and Cell Biology, and Shands Cancer Center, University of Florida, Gainesville, Florida 32610, USA.
Scholz
Axel
A
Morozov
Viacheslav M
VM
Ishov
Alexander M
AM
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy*; D045744:Cell Line, Tumor; D056970:Co-Repressor Proteins; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D005260:Female; D006801:Humans; D051379:Mice; D015162:Micronucleus Tests; D008938:Mitosis / Q000187:drug effects*; D018832:Molecular Chaperones; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D017239:Paclitaxel / Q000378:metabolism / Q000494:pharmacology*; D034622:RNA Interference; D014410:Tumor Stem Cell Assay
D048868:Adaptor Proteins, Signal Transducing; D056970:Co-Repressor Proteins; C106985:DAXX protein, human; D018832:Molecular Chaperones; D009687:Nuclear Proteins; D017239:Paclitaxel