Multinucleated polyploidy drives resistance to Docetaxel chemotherapy in prostate cancer.
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.
Department of Biology, Georgia State University, Atlanta, GA-30303, USA.
Karuna
K
Mittal
Department of Biology, Georgia State University, Atlanta, GA-30303, USA.
Shashi
S
Donthamsetty
Department of Biology, Georgia State University, Atlanta, GA-30303, USA.
Ramneet
R
Kaur
Department of Biology, Georgia State University, Atlanta, GA-30303, USA.
Chunhua
C
Yang
Department of Pathology, West Georgia Hospital, Lagrange, GA, USA.
Meenakshi V
MV
Gupta
Department of Pathology, Emory University School of Medicine, Atlanta, GA, USA.
Michelle D
MD
Reid
Department of Biology, Georgia State University, Atlanta, GA-30303, USA.
Da Hoon
DH
Choi
Department of Biology, Georgia State University, Atlanta, GA-30303, USA.|Novazoi Theranostics, Inc., Rolling Hills Estates, CA 90274, USA.
Padmashree C G
PCG
Rida
Department of Biology, Georgia State University, Atlanta, GA-30303, USA.
Ritu
R
Aneja
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D000077143:Docetaxel; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics; D008297:Male; D051379:Mice; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D011123:Polyploidy; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D043823:Taxoids / Q000008:administration & dosage*; D023041:Xenograft Model Antitumor Assays
C497483:CD44 protein, human; D018960:Hyaluronan Receptors; D043823:Taxoids; D000077143:Docetaxel