Multinucleated polyploidy drives resistance to Docetaxel chemotherapy in prostate cancer

• Type of Material: Article
• Authors: Karuna Mittal, Georgia State University; Shashi Donthamsetty, Georgia State University; Ramneet Kaur, Georgia State University; Chunhua Yang, Georgia State University; Meenakshi V. Gupta, West Georgia Hospital; Michelle Dian Reid, Emory University; Da Hoon Choi, Georgia State University; Padmashree C. G. Rida, Georgia State University; Ritu Aneja, Georgia State University
• Language: English
• Date: 2017-04-25
• Publisher: Cancer Research UK
• Publication Version: Final Published Version
• Copyright Statement: © 2017 Cancer Research UK
• License: Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/bjc.2017.78
• Title of Journal or Parent Work: British Journal of Cancer
• ISSN: 0007-0920
• Volume: 116
• Issue: 9
• Start Page: 1186
• End Page: 1194
• Grant/Funding Information: 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: TUMOR-CELLS; Oncology; CELL-LINES; AGGRESSIVE DISEASE COURSE; NEOSIS; SELF-RENEWAL; PROGRESSION; relapse; Science & Technology; recurrence; prostate cancer; polyploidy; Life Sciences & Biomedicine; docetaxel; multinucleated; SURVIVAL; HELA-CELLS; EXPRESSION; STEM-CELLS
• Research Categories: Health Sciences, Pathology; Health Sciences, Oncology

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.