DNA polymerase theta repression enhances the docetaxel responsiveness in metastatic castration-resistant prostate cancer
Autor: | Jing Quan Zheng, Kuan-Chou Chen, Ruei Chen Hung, Min-Hsuan Lin, Hui Yu Lin, Chia Hao Kuei, Wei Jiunn Lee, Yuan Feng Lin, Che Hsuan Lin, Yen-Lin Chen, Hui Wen Chiu, Long Sheng Lu, Hsun Hua Lee |
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Rok vydání: | 2020 |
Předmět: |
Male
0301 basic medicine DNA polymerase Cell DNA Polymerase Theta Antineoplastic Agents DNA-Directed DNA Polymerase Docetaxel Mice SCID Mice 03 medical and health sciences Prostate cancer 0302 clinical medicine Mice Inbred NOD Prostate Tumor Cells Cultured Animals Humans Medicine RNA Messenger Molecular Biology Gene knockdown Tissue microarray biology business.industry Neoplasms Experimental medicine.disease Prostatic Neoplasms Castration-Resistant 030104 developmental biology medicine.anatomical_structure 030220 oncology & carcinogenesis PC-3 Cells Cancer research biology.protein Molecular Medicine business medicine.drug |
Zdroj: | Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease. 1866:165954 |
ISSN: | 0925-4439 |
Popis: | Objective Docetaxel remains a main treatment for metastatic castration-resistant prostate cancer (mCRPC); however, the development of docetaxel resistance has been found in some mCRPC patients. The aim of this work is to identify an effective biomarker for predicting therapeutic effectiveness of docetaxel in mCRPC patients. Methods We examined DNA polymerase theta (POLQ) expression in The Cancer Genome Atlas (TCGA) database and Tissue microarray. Kaplan-Meier analyses were performed to estimate the prognostic significance of POLQ. A series of functional analyses were conducted in cell lines and xenograft models. Regulated pathways were predicted by Geneset Enrichment Analysis (GSEA) software and further investigated by luciferase reporter and RT-PCR assays. Results We found that POLQ mRNA levels in CRPC tissues was significantly higher than that of other DNA polymerases in non-CRPC prostate tissues. POLQ upregulation was extensively detected in mCRPC and strongly predicted a poor prognosis. POLQ knockdown enhanced docetaxel sensitivity in a cell-based cytotoxicity assay and promoted the therapeutic effect on the tumor growth of metastatic PC-3M cells in xenograft models. The computational simulation by GSEA software significantly predicted the association between POLQ upregulation and the activation of E2F/G2M checkpoint-related pathways. Moreover, luciferase reporter and RT-PCR assays demonstrated that POLQ knockdown downregulated the transcriptional regulatory activity of E2F and repressed E2F/G2M checkpoint-regulated CDK1 in mCRPC cells. Conclusion Our results suggest that POLQ serves as a predictive factor for poor docetaxel response and provide a novel strategy to enhance the anticancer effects of docetaxel therapy by targeting POLQ in mCRPC patients. |
Databáze: | OpenAIRE |
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