Multinucleated polyploidy drives resistance to Docetaxel chemotherapy in prostate cancer.

Autor: Mittal K; Department of Biology, Georgia State University, Atlanta, GA-30303, USA., Donthamsetty S; Department of Biology, Georgia State University, Atlanta, GA-30303, USA., Kaur R; Department of Biology, Georgia State University, Atlanta, GA-30303, USA., Yang C; Department of Biology, Georgia State University, Atlanta, GA-30303, USA., Gupta MV; Department of Pathology, West Georgia Hospital, Lagrange, GA, USA., Reid MD; Department of Pathology, Emory University School of Medicine, Atlanta, GA, USA., Choi DH; Department of Biology, Georgia State University, Atlanta, GA-30303, USA., Rida PCG; Department of Biology, Georgia State University, Atlanta, GA-30303, USA.; Novazoi Theranostics, Inc., Rolling Hills Estates, CA 90274, USA., Aneja R; Department of Biology, Georgia State University, Atlanta, GA-30303, USA.
Jazyk: angličtina
Zdroj: British journal of cancer [Br J Cancer] 2017 Apr 25; Vol. 116 (9), pp. 1186-1194. Date of Electronic Publication: 2017 Mar 23.
DOI: 10.1038/bjc.2017.78
Abstrakt: 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.
Databáze: MEDLINE
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