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Author Notes:
Correspondence: E-mail: raneja@gsu.edu
Acknowledgments: We thank Dr Susan Olson and Nicole Owen from University of Oregon Health and Sciences University for helping us with the fluorescent in situ hybridization experiments.
We gratefully acknowledge Noopur Bhatnagar, Leila Jahromiand and Brian D Melton for assisting with some experiments.
The authors declare no conflict of interest.
Subjects:
Research Funding:
This study was supported by grants to RA from the National Cancer Institutes of Health (U01 CA179671 and R01 CA169127) and a graduate fellowship to KM from the Second Century Initiative Program at Georgia State University.
Keywords:
- Science & Technology
- Life Sciences & Biomedicine
- Oncology
- docetaxel
- polyploidy
- multinucleated
- relapse
- recurrence
- prostate cancer
- AGGRESSIVE DISEASE COURSE
- CELL-LINES
- SELF-RENEWAL
- TUMOR-CELLS
- HELA-CELLS
- STEM-CELLS
- NEOSIS
- EXPRESSION
- PROGRESSION
- SURVIVAL
Multinucleated polyploidy drives resistance to Docetaxel chemotherapy in prostate cancer
Abstract:
Background:Docetaxel is the only FDA-Approved first-line treatment for castration-resistant prostate cancer (CRPC) patients. Docetaxel treatment inevitably leads to tumour recurrence after an initial therapeutic response with generation of multinucleated polyploid (MP ) cells. Here we investigated role of MP cells in clinical relapse of CRPC.Methods:Prostate cancer (PC-3) cells were treated with docetaxel (5 nM) for 3 days followed by a washout and samples were collected at close intervals over 35 days post drug washout. The tumorigenic potential of the giant MP cells was studied by implanting MP cells subcutaneously as tumour xenografts in nude mice.Results:Docetaxel-induced polyploid cells undergo mitotic slippage and eventually spawn mononucleated cells via asymmetric cell division or neosis. Both MP and cells derived from polyploid cells had increased survival signals, were positive for CD44 and were resistant to docetaxel chemotherapy. Although MP cells were tumorigenic in nude mice, these cells took a significantly longer time to form tumours compared with parent PC-3 cells.Conclusions:Generation of MP cells upon docetaxel therapy is an adaptive response of apoptosis-reluctant cells. These giant cells ultimately contribute to the generation of mononucleated aneuploid cells via neosis and may have a fundamental role precipitating clinical relapse and chemoresistance in CRPC.
Copyright information:
© 2017 Cancer Research UK
This is an Open Access work distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License (http://creativecommons.org/licenses/by-nc-sa/4.0/).
