Dataset Information

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.

SUBMITTER: Mittal K

PROVIDER: S-EPMC5418452 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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Publications

Multinucleated polyploidy drives resistance to Docetaxel chemotherapy in prostate cancer.

Mittal Karuna K Donthamsetty Shashi S Kaur Ramneet R Yang Chunhua C Gupta Meenakshi V MV Reid Michelle D MD Choi Da Hoon DH Rida Padmashree C G PCG Aneja Ritu R

British journal of cancer 20170323 9

<h4>Background</h4>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.<h4>Methods</h4>Prostate cancer (PC-3) cells were treated with docetaxel (5 nM) for 3 days followed by a washout and samples were collected at close ...[more]

PMID: 28334734

Similar Datasets

Project description:BackgroundProstate cancer (PC) is a silent but potent killer among men. In 2018, PC accounted for more than 350, 000 death cases while more than 1.2 million cases were diagnosed. Docetaxel, a chemotherapeutic drug belonging to the taxane family of drugs, is one of the most potent drugs in combating advanced PC. However, PC cells often evolve resistance against the regimen. Hence, necessitating the search for complementary and alternative therapies. Quercetin, a ubiquitous phytocompound with numerous pharmacological properties, has been reported to reverse docetaxel resistance (DR) in docetaxel-resistant prostate cancer (DRPC). Therefore, this study aimed to explore the mechanism via which quercetin reverses DR in DRPC using an integrative functional network and exploratory cancer genomic data analyses.ResultsThe putative targets of quercetin were retrieved from relevant databases, while the differentially expressed genes (DEGs) in docetaxel-resistant prostate cancer (DRPC) were identified by analysing microarray data retrieved from the Gene Expression Omnibus (GEO) database. Subsequently, the protein-protein interaction (PPI) network of the overlapping genes between the DEGs and quercetin targets was retrieved from STRING, while the hub genes, which represent the key interacting genes of the network, were identified using the CytoHubba plug-in of Cytoscape. The hub genes were further subjected to a comprehensive analysis aimed at identifying their contribution to the immune microenvironment and overall survival (OS) of PC patients, while their alterations in PC patients were also revealed. The biological roles played by the hub genes in chemotherapeutic resistance include the positive regulation of developmental process, positive regulation of gene expression, negative regulation of cell death, and epithelial cell differentiation among others.ConclusionFurther analysis revealed epidermal growth factor receptor (EGFR) as the most pertinent target of quercetin in reversing DR in DRPC, while molecular docking simulation revealed an effective interaction between quercetin and EGFR. Ultimately, this study provides a scientific rationale for the further exploration of quercetin as a combinational therapy with docetaxel.

Dataset Information

Multinucleated polyploidy drives resistance to Docetaxel chemotherapy in prostate cancer.

Background

Methods

Results

Conclusions

Publications

Multinucleated polyploidy drives resistance to Docetaxel chemotherapy in prostate cancer.

Similar Datasets

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