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Prostate cancer (PCa) is a high‐mortality cancer. Docetaxel (DCT) combined with second‐generation anti‐androgens is considered the golden standard therapy for PCa, whose application is limited for DCT resistance (DR). Therefore, exploring the mechanism of DR is of great importance. In this study, PCa cell lines of PC3 and DU145 were employed, and DR cells were constructed by treatment with graded DCT. CircSLC4A7, miR‐1205, and microtubule‐associated protein tau (MAPT) transfections were established. Cell counting kit‐8 assay was performed to evaluate the cell activity and IC50 of DCT. After being treated with DCT, DR was assessed by colony formation assay, flow cytometry analysis, and terminal transferase‐mediated UTP nick end‐labeling assay. Real‐time quantitative PCR and western blotting analysis evaluated the expression levels of genes. The dual‐luciferase reporter gene assay verified the miR‐1205 binding sites with circSLC4A7 and MAPT. An animal experiment was performed to assess the tumor growth influenced by circSLC4A7. After conducting DR cells and isolated exosomes, we found that not only co‐culture with DR cells but also treatment with DR cells' exosomes would promote the DR of normal cells. Moreover, circSLC4A7 was highly expressed in DR cells and their exosomes. CircSLC4A7 overexpression enhanced DR, represented as raised IC50 of DCT, increased colony formation, and decreased cell apoptosis after DCT treatment, while circSLC4A7 knockdown had the opposite effect. MiR‐1205 was confirmed as a circSLC4A7‐sponged miRNA and miR‐1205 inhibitor reversed the effect of sh‐circSLC4A7. MAPT was further identified as a target of miR‐1205 and had a similar effect with circSLC4A7. The effect of circSLC4A7 on DR was also confirmed by xenograft experiments. Collectively, circSLC4A7 in resistant‐cells‐derived exosomes promotes DCT resistance of PCa via miR‐1205/MAPT axis, which may provide a new treatment strategy for DR of PCa. [ABSTRACT FROM AUTHOR]

Introduction: Transforming acidic coiled-coil containing protein 3 (TACC3) exerts a vital role in cancer progression by modulating cell division and facilitating tumor growth. Given the lack of comprehensive research on the pancancer implications of TACC3, our study aimed to analyze the functional role of TACC3 in pancancer and validate it through experimental investigations in lung adenocarcinoma. Methods: We first employed various bioinformatics techniques to investigate the expression and prognostic significance of TACC3 in pancancer. Subsequently, we analyzed the correlation between TACC3 and immune infiltration, immune checkpoints, drug sensitivity, as well as the prediction of immune therapy response. Finally, we validated the association between TACC3 and the proliferation of lung adenocarcinoma, as well as its resistance to docetaxel, through in vitro experiments. Results: Here, TACC3 exhibited high expression in human cancers and was associated with poor prognosis in various cancer types. It was also involved in immune infiltration and demonstrated a strong predictive ability for immune therapy response. Through drug sensitivity prediction, we further identified a potential association between TACC3 and docetaxel resistance, which was subsequently validated in lung adenocarcinoma. Conclusion: Our investigation of TACC3 revealed its potential as a promising target both for immunosuppression and docetaxel resistance in pancancer, especially in lung adenocarcinoma. [ABSTRACT FROM AUTHOR]

Background and purpose: Castration‐resistant prostate cancer (CRPC) is a common male malignancy that requires new therapeutic strategies due to acquired resistance to its first‐line treatment, docetaxel. The benefits of vitamin D on prostate cancer (PCa) progression have been previously reported. This study aimed to investigate the effects of vitamin D on chemoresistance in CRPC. Experimental approach: Structure function relationships of potent vitamin D analogues were determined. The combination of the most potent analogue and docetaxel was explored in chemoresistant primary PCa spheroids and in a xenograft mouse model derived from a patient with a chemoresistant CRPC. Key results: Here, we show that Xe4MeCF3 is more potent than the natural ligand to induce vitamin D receptor (VDR) transcriptional activities and that it has a larger therapeutic window. Moreover, we demonstrate that VDR agonists restore docetaxel sensitivity in PCa spheroids. Importantly, Xe4MeCF3 reduces tumour growth in a chemoresistant CRPC patient‐derived xenograft. In addition, this treatment targets signalling pathways associated with cancer progression in the remaining cells. Conclusion and implications: Taken together, these results unravel the potency of VDR agonists to overcome chemoresistance in CRPC and open new avenues for the clinical management of PCa. [ABSTRACT FROM AUTHOR]

Objective: Docetaxel (DTX) represents an effective chemotherapeutic agent for treating triple-negative breast cancer (TNBC), but the efficacy is strongly limited by drug resistance. c-MYC-mediated ribosome biogenesis is considered a feasible strategy to confront chemoresistance in BC. We elucidated the impact of CMTM6 on TNBC DTX chemoresistance by governing c-MYC-mediated ribosome biogenesis, and its upstream ceRNA regulatory pathways. Methods: DTX-resistant TNBC cells MDA-MB-231R and HCC1937R were generated by exposing sensitive cells MDA-MB-231 and HCC1937 to escalating doses of DTX. The expression patterns of CMTM6 and c-MYC were assessed by Western blot. The relationships between CMTM6 and miR-340-5p, circUBR5 and miR-340-5p were determined using bioinformatics analysis, luciferase assay, RIP, RNA in situ hybridization and biotin-labeled miR co-precipitation assay. Following ectopic expression and depletion experiments in DTX-resistant cells, cell chemoresistance, apoptosis, colony formation and nascent protein synthesis were evaluated. Results: CMTM6 expression was elevated in DTX-resistant TNBC cells. CMTM6 knockdown enhanced apoptosis of DTX-resistant TNBC cells and increased their sensitivity to DTX by blocking c-MYC-mediated ribosome biogenesis. Mechanistically, miR-340-5p targeted CMTM6 and negatively regulated the expression of CMTM6 in DTX-resistant TNBC cells. Moreover, circUBR5 attenuated the repression on CMTM6 expression as a ceRNA for miR-340-5p. circUBR5 knockdown inactivated c-MYC-mediated ribosome biogenesis, and therefore enhanced DTX efficacy by promoting miR-340-5p binding to CMTM6. Conclusion: circUBR5 knockdown facilitated miR-340-5p-targeted CMTM6 via a ceRNA mechanism, thereby reducing c-MYC-mediated ribosome biogenesis and accelerating chemosensitization of DTX-resistant TNBC cells, which offered a theoretical guideline for clinical research on the feasibility of inhibiting ribosome biogenesis to reduce TNBC chemoresistance.

The development of resistance to Docetaxel (DTX) compromises its therapeutic efficacy and worsens the prognosis of prostate cancer (PCa), while the underlying regulatory mechanism remains poorly understood. In this study, METTL14 was found to be upregulated in DTX‐resistant PCa cells and PCa tissues exhibiting progressive disease during DTX therapy. Furthermore, overexpression of METTL14 promoted the development of resistance to DTX in both in vitro and in vivo. Interestingly, it was observed that the hypermethylation of the E2F1 targeting site within DTX‐resistant PCa cells hindered the binding ability of E2F1 to the promoter region of METTL14, thereby augmenting its transcriptional activity. Consequently, this elevated expression level of METTL14 facilitated m6A‐dependent processing of pri‐miR‐129 and subsequently led to an increase in miR‐129‐5p expression. Our study highlights the crucial role of the E2F1‐METTL14‐miR‐129‐5p axis in modulating DTX resistance in PCa, underscoring METTL14 as a promising therapeutic target for DTX‐resistant PCa patients. [ABSTRACT FROM AUTHOR]

Objective: Circular ribose nucleic acids (circRNAs) are implicated in tumor progression and drug resistance of prostate cancer (PCa). The current work explored the function of circ_0005203 (circTHSD4) in the malignancy and docetaxel (DTX) resistance of PCa. Methods: circTHSD4 expression within PCa as well as matched non-carcinoma samples was measured through real-time reverse transcription-quantitative polymerase chain reaction (RT-qPCR). In addition, a subcellular fraction assay was conducted to determine circTHSD4 subcellular localization within PCa cells. In addition, we performed a Western blot (WB) assay to detect high-mobility-group A2 protein (HMGA2) levels. Besides, functional associations of two molecules were investigated through dual luciferase reporter assay. Cell Counting Kit (CCK)-8, colony formation together with Transwell assay was conducted to assess malignant phenotypes of PCa cells, whereas flow cytometry was performed to determine cell apoptosis. Furthermore, a xenograft mouse model was constructed to verify the effect of circTHSD4 on the carcinogenesis of PCa cells. Results: According to RT-qPCR results, circTHSD4 was up-regulated within PCa tissues and cells, which predicted the dismal prognostic outcome of PCa cases. circTHSD4 silencing within PCa cells markedly suppressed cell growth, migration, and colony formation. circTHSD4 silencing remarkably elevated PCa cell apoptosis and carcinogenesis within the xenograft model. Further, circTHSD4 silencing enhanced docetaxel (DTX) sensitivity in PCa cells. Furthermore, we demonstrated that circTHSD4 modulated the malignancy of PCa cells by regulating HMGA2 expression through sponging miR-203. Conclusion: Together, our findings suggest that circTHSD4 overexpression could promote the malignant phenotype and DTX resistance in PCa through the regulation of the miR-203/HMGA2 axis. [ABSTRACT FROM AUTHOR]

Abstract Background Docetaxel resistance represents a significant obstacle in the treatment of prostate cancer. The intricate interplay between cytokine signalling pathways and transcriptional control mechanisms in cancer cells contributes to chemotherapeutic resistance, yet the underlying molecular determinants remain only partially understood. This study elucidated a novel resistance mechanism mediated by the autocrine interaction of interleukin-11 (IL-11) and its receptor interleukin-11 receptor subunit alpha(IL-11RA), culminating in activation of the JAK1/STAT4 signalling axis and subsequent transcriptional upregulation of the oncogene c-MYC. Methods Single-cell secretion profiling of prostate cancer organoid was analyzed to determine cytokine production profiles associated with docetaxel resistance.Analysis of the expression pattern of downstream receptor IL-11RA and enrichment of signal pathway to clarify the potential autocrine mechanism of IL-11.Next, chromatin immunoprecipitation coupled with high-throughput sequencing (ChIP-seq) was performed to detect the nuclear localization and DNA-binding patterns of phosphorylated STAT4 (pSTAT4). Coimmunoprecipitation and reporter assays were utilized to assess interaction between pSTAT4 and the cotranscription factor CREB-binding protein (CBP) as well as their role in c-MYC transcriptional activity. Results Autocrine secretion of IL-11 was markedly increased in docetaxel-resistant prostate cancer cells. IL-11 stimulation resulted in robust activation of JAK1/STAT4 signalling. Upon activation, pSTAT4 translocated to the nucleus and associated with CBP at the c-MYC promoter region, amplifying its transcriptional activity. Inhibition of the IL-11/IL-11RA interaction or disruption of the JAK1/STAT4 pathway significantly reduced pSTAT4 nuclear entry and its binding to CBP, leading to downregulation of c-MYC expression and restoration of docetaxel sensitivity. Conclusion Our findings identify an autocrine loop of IL-11/IL-11RA that confers docetaxel resistance through the JAK1/STAT4 pathway. The pSTAT4-CBP interaction serves as a critical enhancer of c-MYC transcriptional activity in prostate cancer cells. Targeting this signalling axis presents a potential therapeutic strategy to overcome docetaxel resistance in advanced prostate cancer. Graphical Abstract

The present study aimed to identify the differentially expressed genes (DEGs) and enriched pathways in docetaxel (DTX) resistant breast cancer cell lines by bioinformatics analysis. The microarray dataset GSE28784 was obtained from gene expression omnibus (GEO) database. The differentially expressed genes (DEGs), gene ontology (GO), and Kyoto Encyclopedia of gene and genome (KEGG) pathway analyses were performed with the help of GEO2R and DAVID tools. Furthermore, the protein–protein interaction (PPI) and hub-gene network of DEGs were constructed using STRING and Cytohubba tools. The prognostic values of hub genes were calculated with the help of the Kaplan–Meier plotter database. From the GEO2R analysis, 222 DEGs were identified of which 120 are upregulated and 102 are downregulated genes. In the PPIs network, five up-regulated genes including CCL2, SPARC, CYR61, F3, and MFGE8 were identified as hub genes. It was observed that low expression of six hub genes CXCL8, CYR61, F3, ICAM1, PLAT, and THBD were significantly correlated with poor overall survival of BC patients in survival analysis. miRNA analysis identified that hsa-mir-16-5p, hsa-mir-335-5p, hsa-mir-124-3p, hsa-mir-20a-5p, and hsa-mir-155-5p are the top 5 interactive miRNAs that are commonly interacting with more hub genes with degree score of greater than five. Additionally, drug-gene interaction analysis was performed to identify drugs which are could potentially elevate/lower the expression levels of hub genes. In summary, the gene-miRNAs-TFs network and subsequent correlation of candidate drugs with hub genes may improve individualized diagnosis and help select appropriate combination therapy for DTX-resistant BC in the future. [ABSTRACT FROM AUTHOR]

Docetaxel is the preferred chemotherapeutic agent in patients with castrate‐resistant prostate cancer (CRPC). However, patients eventually develop docetaxel resistance and in the absence of effective treatment options. Consequently, it is essential to investigate the mechanisms generating docetaxel resistance and develop novel alternative therapeutic targets. RNA sequencing was undertaken on docetaxel‐sensitive and docetaxel‐resistant prostate cancer (PCa) cells. Subsequently, chemoresistance, cancer stemness, and lipid metabolism were investigated. To obtain insight into the precise activities and action mechanisms of NOTCH3 in docetaxel‐resistant PCa, immunoprecipitation, mass spectrometry, ChIP, luciferase reporter assay, cell metabolism, and animal experiments were performed. Through RNA sequencing analysis, we found that NOTCH3 expression was markedly higher in docetaxel‐resistant cells relative to parental cells, and that this trend was continued in docetaxel‐resistant PCa tissues. Experiments in vitro and in vivo revealed that NOTCH3 enhanced stemness, lipid metabolism, and docetaxel resistance in PCa. Mechanistically, NOTCH3 is bound to TUBB3 and activates the MAPK signaling pathway. Moreover, NOTCH3 was directly regulated by MEF2A in docetaxel‐resistant cells. Notably, targeting NOTCH3 and the MEF2A/TUBB3 signaling axis was related to docetaxel chemoresistance in PCa. Overall, these results demonstrated that NOTCH3 fostered stemness, lipid metabolism, and docetaxel resistance in PCa via the TUBB3 and MAPK signaling pathways. Therefore, NOTCH3 may be employed as a prognostic biomarker in PCa patients. NOTCH3 could be a therapeutic target for PCa patients, particularly those who have developed docetaxel resistance. [ABSTRACT FROM AUTHOR]

Abstract Purpose To investigate the influence of β-arrestin2 on the docetaxel resistance in castration-resistant prostate cancer (CRPC) and elucidate the underlying molecular mechanisms. Methods PC3 and DU145 cells with stable β-arrestin2 overexpression and C4-2 cells with stable β-arrestin2 knockdown, were constructed via using lentivirus and puromycin selection. MTT and colony formation assays were carried out to investigate the effect of β-arrestin2 expression on the docetaxel resistance of CRPC cells. Glycolysis analysis was used to assess the glycolytic capacity modulated by β-arrestin2. GO enrichment analysis, gene set enrichment analysis and Spearman correlation test were carried out to explore the potential biological function and mechanism via using public data from GEO and TCGA. The expressions of PKM2, Phospho-PKM2, Phospho-ERK1/2 and hnRNP A1 were detected by western blot. Functional blocking experiments were carried out to confirm the roles of PKM2 and hnRNP A1 in the regulation of β-arrestin2’s biological functions via silencing PKM2 or hnRNP A1 expression in cells with stable β-arrestin2 overexpression. Finally, nude mice xenograft models were established to confirm the experimental results of cell experiments. Results β-Arrestin2 significantly decreased the sensitivity of CRPC cells to docetaxel stimulation, through enhancing the phosphorylation and expression of PKM2. Additionally, β-arrestin2 increased PKM2 phosphorylation via the ERK1/2 signaling pathway and induced PKM2 expression in a post-transcriptional manner through an hnRNP A1-dependent PKM alternative splicing mechanism, rather than by inhibiting its ubiquitination degradation. Conclusion Our findings indicate that the β-arrestin2/hnRNP A1/PKM2 pathway could be a promising target for treating docetaxel-resistant CRPC.

Abstract This study was to explore the regulatory effect of long non‐coding RNA LINC01559 on Docetaxel resistance in breast carcinoma (BCa) and its underlying mechanism. In the present study, we found that LINC01559 expression was elevated and LINC01559 overexpression facilitated docetaxel resistance in BCa cells. Moreover, it was revealed that the upregulation of LINC01559 in BCa cells was induced by FTO‐mediated demethylation in an m6A‐YTHDF2‐dependent manner. Additionally, Dual‐luciferase reporter assay confirmed the binding ability between LINC01559 and miR‐1343‐3p, and Pearson correlation analysis showed a negative correlation between them. Particularly, miR‐1343‐3p inhibition partly abolished the suppression on docetaxel resistance in BCa cells caused by LINC01559 knockdown. To sum up, FTO‐mediated epigenetic upregulation of LINC01559 promoted cell resistance to Docetaxel in BCa by negatively regulating miR‐1343‐3p.

Castration-resistant prostate cancer (CRPC) is a fatal disease that evolves from prostate cancer due to drug resistance after long-term androgen deprivation therapy. In this study, we aimed to find novel molecular targets for treating CRPC. Through peptidome, we screened out polypeptides dysregulated in the serum of CRPC patients. According to RT-qPCR analysis and cell viability detection, we chose PDZ and LIM Domain 7 (PDLIM7) as the research object. As demonstrated by loss-of-function assays, silencing of PDLIM7 could suppress CRPC cell proliferation, migration, and angiogenesis. Moreover, PDLIM7 knockdown enhanced the sensitivity of CRPC cells to docetaxel treatment. Subsequently, we found that CBP/p300 increases the H3K27ac level in the PDLIM7 promoter to activate PDLIM7. Mechanism experiments such as IP and western blot revealed that PDLIM7 interacted with YAP1 to induce O-Glycosylation of YAP1 and thus stabilize YAP1 protein. Rescue assays demonstrated that PDLIM7 promoted the malignant processes of CRPC cells through YAP1. Finally, an animal study validated that PDLIM7 aggravated tumor growth. In conclusion, our findings highlighted the oncogenic role of PDLIM7 upregulated by CBP/p300-induced H3K27ac enhancement in CRPC by stabilizing YAP1.

Purpose: To investigate the influence of β-arrestin2 on the docetaxel resistance in castration-resistant prostate cancer (CRPC) and elucidate the underlying molecular mechanisms. Methods: PC3 and DU145 cells with stable β-arrestin2 overexpression and C4-2 cells with stable β-arrestin2 knockdown, were constructed via using lentivirus and puromycin selection. MTT and colony formation assays were carried out to investigate the effect of β-arrestin2 expression on the docetaxel resistance of CRPC cells. Glycolysis analysis was used to assess the glycolytic capacity modulated by β-arrestin2. GO enrichment analysis, gene set enrichment analysis and Spearman correlation test were carried out to explore the potential biological function and mechanism via using public data from GEO and TCGA. The expressions of PKM2, Phospho-PKM2, Phospho-ERK1/2 and hnRNP A1 were detected by western blot. Functional blocking experiments were carried out to confirm the roles of PKM2 and hnRNP A1 in the regulation of β-arrestin2's biological functions via silencing PKM2 or hnRNP A1 expression in cells with stable β-arrestin2 overexpression. Finally, nude mice xenograft models were established to confirm the experimental results of cell experiments. Results: β-Arrestin2 significantly decreased the sensitivity of CRPC cells to docetaxel stimulation, through enhancing the phosphorylation and expression of PKM2. Additionally, β-arrestin2 increased PKM2 phosphorylation via the ERK1/2 signaling pathway and induced PKM2 expression in a post-transcriptional manner through an hnRNP A1-dependent PKM alternative splicing mechanism, rather than by inhibiting its ubiquitination degradation. Conclusion: Our findings indicate that the β-arrestin2/hnRNP A1/PKM2 pathway could be a promising target for treating docetaxel-resistant CRPC. [ABSTRACT FROM AUTHOR]

Abstract Background To investigate underlying mechanism of JMJD2A in regulating cytoskeleton remodeling in castration-resistant prostate cancer (CRPC) resistant to docetaxel. Methods Tissue samples from CRPC patients were collected, and the expression of JMJD2A, miR-34a and cytoskeleton remodeling-related proteins were evaluated by qPCR, western blot and immunohistochemistry, and pathological changes were observed by H&E staining. Further, JMJD2A, STMN1 and TUBB3 were knocked down using shRNA in CRPC cell lines, and cell viability, apoptosis and western blot assays were performed. The interaction between miR-34a/STMN1/β3-Tubulin was analyzed with dual-luciferase reporter and co-immunoprecipitation assays. Results In clinical experiment, the CRPC-resistant group showed higher expression of JMJD2A, STMN1, α-Tubulin, β-Tubulin and F-actin, and lower expression of miR-34a and β3-Tubulin compared to the sensitive group. In vitro experiments showed that JMJD2A could regulate cytoskeletal remodeling through the miR-34a/STMN1/β3-Tubulin axis. The expression of miR-34a was elevated after knocking down JMJD2A, and miR-34a targeted STMN1. The overexpression of miR-34a was associated with a decreased expression of STMN1 and elevated expression of β3-Tubulin, which led to the disruption of the microtubule network, decreased cancer cell proliferation, cell cycle arrest in the G0/G1 phase, and increased apoptosis. Conclusion JMJD2A promoted docetaxel resistance in prostate cancer cells by regulating cytoskeleton remodeling through the miR-34a/STMN1/β3-Tubulin axis.

Resistance to docetaxel is a major problem to the success of docetaxel-based therapies for breast cancer. The present study was to identify the role of circABCB1 in altering the docetaxel resistance properties. Reverse transcription-quantitative PCR (qRT-PCR) was performed to quantify circABCB1 and miR-153-3p. The effects of circABCB1 on the viability, apoptosis and migration/invasion of docetaxel-resistant and -sensitive cells were investigated by cell function experiments, including Cell Counting Kit-8 and Transwell assays. Correlation between circABCB1 and the docetaxel-treated outcome was analyzed by multivariate Cox regression analysis, in addition to Kaplan-Meier analysis of time to treatment failure (TTF). The targeting relationship between circABCB1 and miR-153-3p was predicted and verified by dual-luciferase reporter assay and RNA immunoprecipitation. CircABCB1 was highly expressed in cancerous tissues, as well as the docetaxel-sensitive group and cells. The overexpression of circABCB1 contributed to cell viability, docetaxel-resistance and migration/invasion, but inhibited apoptosis. CircABCB1 can sponge miR-153-3p. CircABCB1 contributed to the docetaxel resistance of breast cancer, maybe via the miR-153-3p. [ABSTRACT FROM AUTHOR]

This study was to explore the regulatory effect of long non‐coding RNA LINC01559 on Docetaxel resistance in breast carcinoma (BCa) and its underlying mechanism. In the present study, we found that LINC01559 expression was elevated and LINC01559 overexpression facilitated docetaxel resistance in BCa cells. Moreover, it was revealed that the upregulation of LINC01559 in BCa cells was induced by FTO‐mediated demethylation in an m6A‐YTHDF2‐dependent manner. Additionally, Dual‐luciferase reporter assay confirmed the binding ability between LINC01559 and miR‐1343‐3p, and Pearson correlation analysis showed a negative correlation between them. Particularly, miR‐1343‐3p inhibition partly abolished the suppression on docetaxel resistance in BCa cells caused by LINC01559 knockdown. To sum up, FTO‐mediated epigenetic upregulation of LINC01559 promoted cell resistance to Docetaxel in BCa by negatively regulating miR‐1343‐3p. [ABSTRACT FROM AUTHOR]

Docetaxel (DTX) plays an important role in treating advanced prostate cancer (PCa). However, nearly all patients receiving DTX therapy ultimately progress to DTX resistance. How to address DTX resistance in PCa remains a key challenge for all urologists. Small ankyrin 1 (sAnk1) is an integral membrane protein in the endoplasmic reticulum. In the present study, we identified that sAnk1 is upregulated in PCa tissues and is positively associated with DTX therapy resistance in PCa. Further investigation demonstrated that overexpression of sAnk1 can significantly increase the DTX‐resistant ability of PCa cells in vitro and in vivo. In addition, overexpression of sAnk1 could enhance oxidative phosphorylation (OXPHOS) levels in PCa cells, which was consistent with the higher OXPHOS levels observed in DTX‐resistant PCa cells as compared to DTX‐sensitive PCa cells. sAnk1 was also found to interact with polypyrimidine‐tract‐binding protein (PTBP1), an alternative splicing factor, and suppressed PTBP1‐mediated alternative splicing of the pyruvate kinase gene (PKM). Thus, overexpression of sAnk1 decreased the ratio of PKM2/PKM1, enhanced the OXPHOS level, and ultimately promoted the resistance of PCa cells to DTX. In summary, our data suggest that sAnk1 enhances DTX resistance in PCa cells.

Background: To investigate underlying mechanism of JMJD2A in regulating cytoskeleton remodeling in castration-resistant prostate cancer (CRPC) resistant to docetaxel. Methods: Tissue samples from CRPC patients were collected, and the expression of JMJD2A, miR-34a and cytoskeleton remodeling-related proteins were evaluated by qPCR, western blot and immunohistochemistry, and pathological changes were observed by H&E staining. Further, JMJD2A, STMN1 and TUBB3 were knocked down using shRNA in CRPC cell lines, and cell viability, apoptosis and western blot assays were performed. The interaction between miR-34a/STMN1/β3-Tubulin was analyzed with dual-luciferase reporter and co-immunoprecipitation assays. Results: In clinical experiment, the CRPC-resistant group showed higher expression of JMJD2A, STMN1, α-Tubulin, β-Tubulin and F-actin, and lower expression of miR-34a and β3-Tubulin compared to the sensitive group. In vitro experiments showed that JMJD2A could regulate cytoskeletal remodeling through the miR-34a/STMN1/β3-Tubulin axis. The expression of miR-34a was elevated after knocking down JMJD2A, and miR-34a targeted STMN1. The overexpression of miR-34a was associated with a decreased expression of STMN1 and elevated expression of β3-Tubulin, which led to the disruption of the microtubule network, decreased cancer cell proliferation, cell cycle arrest in the G0/G1 phase, and increased apoptosis. Conclusion: JMJD2A promoted docetaxel resistance in prostate cancer cells by regulating cytoskeleton remodeling through the miR-34a/STMN1/β3-Tubulin axis. [ABSTRACT FROM AUTHOR]

Simple Summary: Long non-coding RNA plays an essential role in the occurrence and development of prostate cancer. Drug re-sistance in tumor cells is one of the main reasons that affects the effectiveness of chemotherapy in cancer patients. The immunogenicity of the tumor is edited, and various immunosuppressive mechanisms that enable disease pro-gression are acquired, causing the tumor cells to evade the surveillance of the immune system, leading to immune evasion and drug resistance of the tumor cells. The lncRNA related to cellular immunity was obtained by bioin-formatics analysis, and the lncRNA-miRNA-mRNA regulatory network was constructed to study the mechanism of chemotherapy resistance in colon cancer cells and to obtain key genes for tumor cell resistance. Long noncoding RNAs (LncRNAs) are very important in the way that docetaxel resistance (DR) happens in prostate cancer (PCa) patients. ImmuneScore and StromalScore were calculated using PCa-related expression data from TCGA and the ESTIMATE algorithm. We finally found the DEGs that were related to the immune system and the stroma of the patients by making profiles of the DEGs in ImmuneScore and StromalScore. The CancerSubtypes algorithm identified prognosis-related PCa subtypes, and the GSVA assessed their pathway activity. A UniCox regression analysis was used to identify a prognosis-related differential gene set. We then used intersection analysis to identify immunological and prognostic (IP)-related genes (IPGs). The coexpression of long noncoding RNAs (lncRNAs) and IPGs was used to identify IP-related lncRNAs (IPLs). Three methods (SVM-RFE, random forest, and LASSO) were used to find genes that overlap in the GEO database. A gene signature was then validated by building an ROC curve. CIBERSORT technology was used to look at the possibility of a link between the gene signature and immune cells. LncRNA–miRNA pairs and miRNA–mRNA pairs from the miRDB and TargetScan databases were used to construct the ERVH48-1-miR-4784-WNT2B ceRNA regulation network. The concentration of docetaxel elevated the expression of ERVH48-1. Overexpression of ERVH48-1 increased PCa-DR cell proliferation, invasion, and migration while inhibiting apoptosis. ERVH48-1 increased the tumorigenicity of PCa-DR cells in nude mice. ERVH48-1, acting as a ceRNA, targeted miR-4784 to increase WNT2B expression. ICG001 therapy increased Wnt/-catenin signaling activity in PCa-DR cells by inhibiting ERVH48-1. Finally, ERVH48-1 increased docetaxel resistance in a WNT2B-dependent manner via the miR-4784/Wnt/-catenin pathway. [ABSTRACT FROM AUTHOR]

Abstract Background Docetaxel (DTX) is the most widely prescribed first-line chemotherapy for advanced prostate cancer (PCa). Unfortunately, DTX resistance invariably emerges, leading to worse prognosis of PCa. Growing evidence has shown that circRNAs had complex spatiotemporal specificity during the tumor development and oncogenesis. This study was designed to investigate the biological functions and possible molecular mechanisms of circRNAs in DTX resistance of PCa. Methods circRNAs in established DTX-resistant DU145 cell line were identified by RNA sequencing. Biological function of circCYP24A1 was verified in vitro and in vivo. The potential role of circCYP24A1 in the development of DTX-resistant PCa was investigated via dual-luciferase reporter assays, RIP assays and RNA pull-down assays. Univariate and multivariate logistic regression analyses was used to predict DTX-chemotherapy response based on patients’ clinical and biological information. Results CircCYP24A1 was identified to be upregulated in DTX-resistant DU145 cells. Upregulated circCYP24A1 was found to suppress the DTX chemosensitivity in vitro and in vivo. Furthermore, we found that circCYP24A1 promoted DTX resistance in PCa via regulating ALDH1A3 expression by sponging miR-1301-3p and activating PI3K/AKT/mTOR signaling pathway. Statistical analyses elucidated that circCYP24A1 was an independent risk factor to predict DTX response (OR = 0.165; 95% CI: 0.038–0.723; P = 0.017). Conclusions This study demonstrated that circCYP24A played an essential role in DTX resistance in PCa, suggesting that circCYP24A1 could be a promising biomarker to predict DTX response and a potential therapeutic target in PCa patients resistant to DTX chemotherapy.

Docetaxel (DTX) represents an effective chemotherapeutic agent for treating triple-negative breast cancer (TNBC), but the efficacy is strongly limited by drug resistance. c-MYC-mediated ribosome biogenesis is considered a feasible strategy to confront chemoresistance in BC. We elucidated the impact of CMTM6 on TNBC DTX chemoresistance by governing c-MYC-mediated ribosome biogenesis, and its upstream ceRNA regulatory pathways. DTX-resistant TNBC cells MDA-MB-231R and HCC1937R were generated by exposing sensitive cells MDA-MB-231 and HCC1937 to escalating doses of DTX. The expression patterns of CMTM6 and c-MYC were assessed by Western blot. The relationships between CMTM6 and miR-340-5p, circUBR5 and miR-340-5p were determined using bioinformatics analysis, luciferase assay, RIP, RNA in situ hybridization and biotin-labeled miR co-precipitation assay. Following ectopic expression and depletion experiments in DTX-resistant cells, cell chemoresistance, apoptosis, colony formation and nascent protein synthesis were evaluated. CMTM6 expression was elevated in DTX-resistant TNBC cells. CMTM6 knockdown enhanced apoptosis of DTX-resistant TNBC cells and increased their sensitivity to DTX by blocking c-MYC-mediated ribosome biogenesis. Mechanistically, miR-340-5p targeted CMTM6 and negatively regulated the expression of CMTM6 in DTX-resistant TNBC cells. Moreover, circUBR5 attenuated the repression on CMTM6 expression as a ceRNA for miR-340-5p. circUBR5 knockdown inactivated c-MYC-mediated ribosome biogenesis, and therefore enhanced DTX efficacy by promoting miR-340-5p binding to CMTM6. circUBR5 knockdown facilitated miR-340-5p-targeted CMTM6 via a ceRNA mechanism, thereby reducing c-MYC-mediated ribosome biogenesis and accelerating chemosensitization of DTX-resistant TNBC cells, which offered a theoretical guideline for clinical research on the feasibility of inhibiting ribosome biogenesis to reduce TNBC chemoresistance. [ABSTRACT FROM AUTHOR]

Abstract Background Acquisition of the chemoresistance to docetaxel (DTX), a microtubule-targeting agent, has been a huge obstacle in treatment for metastatic castration-resistant prostate cancer (mCRPC). Recently, strategies targeting the mitosis error correction mechanism including chromosomal passenger complex (CPC) were reported to reverse the resistance to microtubule-targeting anticancer agents. Meanwhile, accumulating evidence indicated the important roles of circRNAs in DTX resistance of prostate cancer (PCa). However, whether circRNAs could regulate DTX chemosensitivity by affecting the mitosis error correction mechanism remains unclear. Methods Expression patterns of circ_0004087 and BUB1 were determined through mining the public circRNA datasets and performing western blot and qRT-PCR assays. Agarose gel electrophoresis, Sanger sequencing, and RNase R treatment were conducted to examine the circular characteristics of circ_0004087. CircRNA pull-down, mass spectrometry analysis, Co-IP, and dual-luciferase reporter assays were performed to uncover the interaction among circ_0004087, SND1, and MYB. The effects of circ_0004087 and BUB1 on docetaxel-based chemotherapy were explored by flow cytometry and in vivo drug studies upon xenografted tumor model. Results In the present study, we revealed the profound interaction between a novel circRNA, circ_0004087, and the mitosis error correction mechanism. Mechanistically, circ_0004087 binding with transcriptional coactivator SND1 could stimulate the transactivation of MYB and enhance the expression of downstream target BUB1. In turn, elevated BUB1 expression further recruited CPC to centromeres and guaranteed the error-free mitosis of PCa cells. Biologically, the overexpression of circ_0004087 conferred while the knockdown impaired DTX resistance in PCa cells. Conclusions Our study uncovered the crucial role of circ_0004087/SND1/MYB/BUB1 axis in modulating the error mitosis correction mechanism and DTX chemoresistance, suggesting that circ_0004087 may serve as a valuable prognostic biomarker and a potential therapeutic target in DTX-resistant PCa patients.

Background: Docetaxel (DCT) is widely used in clinical practice, but the drug resistance of breast cancer patients has become an important reason to limit its clinical efficacy. Chan’su is a commonly used traditional Chinese medicine for the treatment of breast cancer. Bufalin (BUF) is a bioactive polyhydroxy steroid extracted from chan’su and has strong antitumor activity, but there are few studies on reversing drug resistance in breast cancer. The aim of this study is to determine whether BUF can reverse the drug resistance to DCT and restore efficacy in breast cancer. Methodology: The reversal index of BUF was detected by Cell Counting Kit-8 (CCK-8) assays. The effects of BUF on enhancing the apoptosis of DCT were detected by flow cytometry and Western Blot (WB), and the main differential expression levels of sensitive and resistant strains were detected by high-throughput sequencing. Rhodamine 123 assay, WB and ATP Binding Cassette Subfamily B Member 1 (ABCB1) ATPase activity experiments were used to detect the effect of BUF on ABCB1. The nude mouse orthotopic model was constructed to investigate the reversal effect of BUF on DCT resistance in vivo. Results: With BUF intervention, the sensitivity of drug-resistant cell lines to DCT was increased. BUF can inhibit the expression of ABCB1 protein, increase the drug accumulation of DCT in drug-resistant strains, and reduce the ATPase activity of ABCB1. Animal experiments show that BUF can inhibit the growth of drug-resistant tumors in an orthotopic model of breast cancer and decrease the expression of ABCB1. Conclusion: BUF can reverse ABCB1-mediated docetaxel resistance in breast cancer.

Background/aim: Docetaxel combined with gemcitabine is a second-line treatment for soft-tissue sarcoma; however, its effectiveness is limited because of docetaxel resistance. The objective of the present study was to determine the potential of recombinant methioninase (rMETase) to enhance the efficacy of docetaxel on high-docetaxel-resistant human fibrosarcoma cells in vitro., Materials and Methods: Docetaxel-resistant HT1080 (DTR-HT1080) human fibrosarcoma cells were established by culturing them in by progressively increasing concentrations of docetaxel from 0.02 to 9 nM in vitro. The IC 50 values for docetaxel and rMETase, as well as the efficacy of their combination, in inhibiting HT1080 human fibrosarcoma cells, DTR-HT1080 cells, and Hs27 normal human fibroblasts were determined. Four experimental groups were examined in vitro: control group without treatment; docetaxel alone; rMETase alone; docetaxel combined with rMETase., Results: The IC 50 of docetaxel for DTR-HT1080 cells was 7.57 nM, compared to the parental HT1080 cells with an IC 50 of 1.68 nM, a 4.5-fold increase. The IC 50 of docetaxel on Hs27 fibroblasts was 4.46 nM. The IC 50 of rMETase on HT1080 cells was 0.75 U/ml (data from [6]). The IC 50 of rMETase on DTR-HT1080 cells was 0.55 U/ml. The IC 50 of rMETase on Hs27 fibroblasts was 0.93 U/ml (data from [6]). Docetaxel (1.68 nM [IC 50 ]) plus rMETase (0.75 U/ml [IC 50 ]) synergistically reduced the viability of HT1080 cells (p<0.05). In contrast, docetaxel (4.46 nM) plus rMETase (0.93 U/ml) did not reduce the viability of Hs27 fibroblasts, compared to either agent alone. The combination of rMETase (0.55 U/ml [IC 50 ]) and docetaxel (1.68 nM [IC 50 of the parental cells]) overcame docetaxel resistance of DTR-HT1080 cells, resulting in an inhibition of 48.1% compared to docetaxel alone (6.8%) or rMETase alone (37.5%) (p<0.05). rMETase thus increased the efficacy of docetaxel 7-fold on docetaxel-resistant human fibrosarcoma cells., Conclusion: The combination of docetaxel and rMETase was synergistic on HT1080 fibrosarcoma cells, but not normal fibroblasts. rMETase plus docetaxel synergistically reduced the high docetaxel resistance of DTR-HT1080 cells. The present results indicate the clinical potential of rMETase to reduce docetaxel resistance in soft-tissue sarcoma patients in the future., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: Docetaxel combined with gemcitabine is a second-line therapy for osteosarcoma, but its efficacy is limited by the development of docetaxel resistance. The aim of the present study was to determine whether recombinant methioninase (rMETase) could reverse docetaxel resistance developed in osteosarcoma cells., Materials and Methods: Docetaxel-resistant 143B (DTR-143B) osteosarcoma cells were established by treating the parental 143B cells to increasing docetaxel concentrations (0.14-24 nM) over 5 months. The 50% inhibitory concentration (IC 50 ) of docetaxel and rMETase as well as their combination on human osteosarcoma cells 143B and DTR-143B were determined. Four groups were analysed in vitro: untreated control; docetaxel; rMETase; docetaxel plus rMETase., Results: The IC 50 value of docetaxel for DTR-143B cells was 31.1 nM, compared to 4.38 nM for the parental 143B cells, a 7-fold increase. The combination of rMETase (0.53 U/ml) and docetaxel (4.38 nM) sensitized DTR-143B cells to docetaxel resulting in an inhibition of 73.7% compared to docetaxel alone (7.3%) or rMETase alone (54.6%) (p<0.05). rMETase thus increased the efficacy of docetaxel 10-fold on docetaxel-resistant osteosarcoma cells., Conclusion: rMETase reversed docetaxel resistance of DTR-143B in vitro. The present results indicate the clinical potential of rMETase to overcome docetaxel resistance in osteosarcoma patients., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Chemoresistance is the major cause of therapeutic failure in human triple negative breast carcinoma (TNBC). Docetaxel (DOC), a first-line therapeutic drug in TNBC treatment, is limited for long-term use due to the development of chemoresistance. Thus, overcoming chemoresistance of DOC remains an important challenge to improve patient’s outcome of TNBC. In this study, we aimed to investigate the molecular mechanism behind DOC chemoresistance and the possible therapeutic effects of miRNAs. Utilizing qRT-PCR analysis, we discovered that miR-1205 is gradually downregulated in human triple negative breast carcinoma MDA-MB-231 and docetaxel-resistant MDA-MB-231 (MDA-MB-231/DOC) cells compared with Hs 578Bst normal human breast fibroblasts. Cell viability, cell cycle and apoptosis assays in MDA-MB-231/DOC cells indicated that miR-1205 overexpression enhances docetaxel sensitivity by reducing cell viability as well as inducing G2/M cell cycle arrest and cell apoptosis. Western blot analysis, dual-luciferase reporter assay, co-immunoprecipitation assay and chromatin immunoprecipitation assay revealed that miR-1205 overexpression disrupts the stable complex formation of DNAJB1, mutp53 and TAp63 by directly reducing DNAJB1 expression, which abates the sequestrating effect of mutp53 on TAp63, thereby leading to the enhanced DOC sensitivity in MDA-MB-231/DOC cells. Our findings demonstrate the role of the miR-1205/DNAJB1 axis in the docetaxel resistance of TNBC, which may offer a promising therapeutic approach to resolve docetaxel resistance in TNBC.

Abstract Although docetaxel (DTX) confers significant survival benefits in patients with castration‐resistant prostate cancer (CRPC), resistance to DTX inevitably occurs. Therefore, clarifying the mechanisms of DTX resistance may improve survival in patients with CRPC. Claspin plays a pivotal role in DNA replication stress and damage responses and is an essential regulator for the S‐phase checkpoint. CLSPN is an oncogenic gene that contributes to tumor proliferation in several human solid tumors. However, the clinical significance of claspin in prostate cancer (PCa) has not been examined. The present study aimed to elucidate the role of claspin and its relationship with DTX resistance in PCa. We immunohistochemically analyzed the expression of claspin in 89 PCa cases, of which 31 (35%) were positive for claspin. Claspin‐positive cases were associated with higher Gleason score, venous invasion, and perineural invasion. Kaplan–Meier analysis showed that high claspin expression was related to poor prostate‐specific antigen (PSA) relapse‐free prognosis. In a public database, high CLSPN expression was associated with poor PSA relapse‐free prognosis, Gleason score, T stage, lymph node metastasis, CRPC, and metastatic PCa. Claspin knockdown by siRNA decreased cell proliferation, upregulated DTX sensitivity, and suppressed the expression of Akt, Erk1/2, and CHK1 phosphorylation in DU145 and PC3 cell lines. Furthermore, claspin expression was much more upregulated in DTX‐resistant DU145 (DU145‐DR) than in parental DU145 cells. Claspin knockdown significantly upregulated the sensitivity to DTX in DU145‐DR cells. These results suggest that claspin plays an important role in PCa tumor progression and DTX resistance.

Background: Docetaxel (DTX) is the most widely prescribed first-line chemotherapy for advanced prostate cancer (PCa). Unfortunately, DTX resistance invariably emerges, leading to worse prognosis of PCa. Growing evidence has shown that circRNAs had complex spatiotemporal specificity during the tumor development and oncogenesis. This study was designed to investigate the biological functions and possible molecular mechanisms of circRNAs in DTX resistance of PCa. Methods: circRNAs in established DTX-resistant DU145 cell line were identified by RNA sequencing. Biological function of circCYP24A1 was verified in vitro and in vivo. The potential role of circCYP24A1 in the development of DTX-resistant PCa was investigated via dual-luciferase reporter assays, RIP assays and RNA pull-down assays. Univariate and multivariate logistic regression analyses was used to predict DTX-chemotherapy response based on patients' clinical and biological information. Results: CircCYP24A1 was identified to be upregulated in DTX-resistant DU145 cells. Upregulated circCYP24A1 was found to suppress the DTX chemosensitivity in vitro and in vivo. Furthermore, we found that circCYP24A1 promoted DTX resistance in PCa via regulating ALDH1A3 expression by sponging miR-1301-3p and activating PI3K/AKT/mTOR signaling pathway. Statistical analyses elucidated that circCYP24A1 was an independent risk factor to predict DTX response (OR = 0.165; 95% CI: 0.038–0.723; P = 0.017). Conclusions: This study demonstrated that circCYP24A played an essential role in DTX resistance in PCa, suggesting that circCYP24A1 could be a promising biomarker to predict DTX response and a potential therapeutic target in PCa patients resistant to DTX chemotherapy. [ABSTRACT FROM AUTHOR]

Prostate cancer is the most common cancer among men, and developed metastasis spread to parts of the body. Clinically, prostate cancer can develop resistance to chemotherapy drugs, and generally, the initial treatment for metastatic prostate cancer is androgen deprivation therapy in combination with chemotherapy. This study aimed to further investigate the signaling mechanisms of Bicalutamide (BCLT) with TRAIL combination in resistance to Docetaxel (DX) on the prostate cancer cell. The human prostate cancer cell lines PC3 were generated by initially treating with DX for docetaxel resistance prostate cancer cells (PC3/DX). PC3/DX cells were transfected pAR plasmid for modeling androgen-dependent docetaxel resistance prostate cancer cells (PC3/DX/AR+) and were incubated with BCLT (2.5 µM) and/or TRAIL (2.5 ng/mL). After the treatment, cell proliferation was determined with an MTT assay. Apoptotic cells were investigated with AO/EB staining by fluorescence microscope. Levels of Caspase-3, Caspase-8, AR, TNF-a protein and gene expression were evaluated. We found apoptosis increased with TRAIL (5 ng/mL) in PC3/DX cells, whereas with the combination of 2.5 ng/mL TRAIL and BCLT (2.5 µM) in PC3/DX/AR+ cells. TNF-a protein and gene expression levels increase with TRAIL in PC3/DX and PC3/DX/AR+ cells. AR protein and gene expression levels increased with BCLT and TRAIL PC3/DX/AR+ cells. Our results indicate that BCLT and TRAIL combination has potential agents for inhibiting docetaxel resistance prostate cancer growth and metastasis. [ABSTRACT FROM AUTHOR]

Background: Acquisition of the chemoresistance to docetaxel (DTX), a microtubule-targeting agent, has been a huge obstacle in treatment for metastatic castration-resistant prostate cancer (mCRPC). Recently, strategies targeting the mitosis error correction mechanism including chromosomal passenger complex (CPC) were reported to reverse the resistance to microtubule-targeting anticancer agents. Meanwhile, accumulating evidence indicated the important roles of circRNAs in DTX resistance of prostate cancer (PCa). However, whether circRNAs could regulate DTX chemosensitivity by affecting the mitosis error correction mechanism remains unclear. Methods: Expression patterns of circ_0004087 and BUB1 were determined through mining the public circRNA datasets and performing western blot and qRT-PCR assays. Agarose gel electrophoresis, Sanger sequencing, and RNase R treatment were conducted to examine the circular characteristics of circ_0004087. CircRNA pull-down, mass spectrometry analysis, Co-IP, and dual-luciferase reporter assays were performed to uncover the interaction among circ_0004087, SND1, and MYB. The effects of circ_0004087 and BUB1 on docetaxel-based chemotherapy were explored by flow cytometry and in vivo drug studies upon xenografted tumor model. Results: In the present study, we revealed the profound interaction between a novel circRNA, circ_0004087, and the mitosis error correction mechanism. Mechanistically, circ_0004087 binding with transcriptional coactivator SND1 could stimulate the transactivation of MYB and enhance the expression of downstream target BUB1. In turn, elevated BUB1 expression further recruited CPC to centromeres and guaranteed the error-free mitosis of PCa cells. Biologically, the overexpression of circ_0004087 conferred while the knockdown impaired DTX resistance in PCa cells. Conclusions: Our study uncovered the crucial role of circ_0004087/SND1/MYB/BUB1 axis in modulating the error mitosis correction mechanism and DTX chemoresistance, suggesting that circ_0004087 may serve as a valuable prognostic biomarker and a potential therapeutic target in DTX-resistant PCa patients. [ABSTRACT FROM AUTHOR]

Docetaxel (DTX) was the first chemotherapeutic agent to demonstrate significant efficacy in the treatment of men with metastatic castration-resistant prostate cancer. However, response to DTX is generally short-lived, and relapse eventually occurs due to emergence of drug-resistance. We previously established two DTX-resistant prostate cancer cell lines, LNCaPR and C4-2BR, derived from the androgen‐dependent LNCaP cell line, and from the LNCaP lineage-derived androgen-independent C4-2B sub-line, respectively. Using an unbiased drug screen, we identify itraconazole (ITZ), an oral antifungal drug, as a compound that can efficiently re-sensitize drug-resistant LNCaPR and C4-2BR prostate cancer cells to DTX treatment. ITZ can re-sensitize multiple DTX-resistant cell models, not only in prostate cancer derived cells, such as PC-3 and DU145, but also in docetaxel-resistant breast cancer cells. This effect is dependent on expression of ATP-binding cassette (ABC) transporter protein ABCB1, also known as P-glycoprotein (P-gp). Molecular modeling of ITZ bound to ABCB1, indicates that ITZ binds tightly to the inward-facing form of ABCB1 thereby inhibiting the transport of DTX. Our results suggest that ITZ may provide a feasible approach to re-sensitization of DTX resistant cells, which would add to the life-prolonging effects of DTX in men with metastatic castration-resistant prostate cancer. [ABSTRACT FROM AUTHOR]

Docetaxel (DTX) was the first chemotherapeutic agent to demonstrate significant efficacy in the treatment of men with metastatic castration-resistant prostate cancer. However, response to DTX is generally short-lived, and relapse eventually occurs due to emergence of drug-resistance. We previously established two DTX-resistant prostate cancer cell lines, LNCaPR and C4-2BR, derived from the androgen‐dependent LNCaP cell line, and from the LNCaP lineage-derived androgen-independent C4-2B sub-line, respectively. Using an unbiased drug screen, we identify itraconazole (ITZ), an oral antifungal drug, as a compound that can efficiently re-sensitize drug-resistant LNCaPR and C4-2BR prostate cancer cells to DTX treatment. ITZ can re-sensitize multiple DTX-resistant cell models, not only in prostate cancer derived cells, such as PC-3 and DU145, but also in docetaxel-resistant breast cancer cells. This effect is dependent on expression of ATP-binding cassette (ABC) transporter protein ABCB1, also known as P-glycoprotein (P-gp). Molecular modeling of ITZ bound to ABCB1, indicates that ITZ binds tightly to the inward-facing form of ABCB1 thereby inhibiting the transport of DTX. Our results suggest that ITZ may provide a feasible approach to re-sensitization of DTX resistant cells, which would add to the life-prolonging effects of DTX in men with metastatic castration-resistant prostate cancer.

Abstract Background Mesenchymal stem cells (MSCs) have been proved to drive castration resistant prostate cancer (CRPC). In this study, we aim to investigate the contribution of MSCs to the development of docetaxel resistance in CRPC cells and its potential mechanisms. Methods The effect of MSCs on CRPC cells resistance to docetaxel was determined using in vivo and in vitro approaches. CCK8 and PI/Annexin V-FITC assay were used to examined the cell viability and apoptosis. The concentration of transforming growth factor-β1 was measured by enzyme-linked immunosorbent assay and small interfering RNA was used for functional analyses. Results MSCs significantly reduced the sensitivity of CRPC cells to docetaxel-induced proliferation inhibition and apoptosis promotion in vivo and in vitro. CRPC cells cocultured with MSCs under docetaxel administration have an increased autophagy activation, while autophagy inhibitor could effectively reversed MSCs-induced resistance to docetaxel. Additionally, MSCs-induced CRPC cell autophagy increase under docetaxel administration depends on MSCs secreting TGF-β1 and inhibition of TGF-β1 secretion in MSCs could consequently increase the sensitivity of CRPC cells to docetaxel. Conclusions These results suggest that docetaxel administrated CRPC cells may elicit MSCs secreting TGF-β1 increase, which desensitizes CRPC to docetaxel chemotherapy accelerating chemoresistance occurrence via inducing cell autophagy.

Baseline or acquired resistance to docetaxel (DOC) represents a significant risk for patients with metastatic prostate cancer (PC). In the last years, novel therapy regimens have been approved providing reasonable alternatives for DOC‐resistant patients making prediction of DOC resistance of great clinical importance. We aimed to identify serum biomarkers, which are able to select patients who will not benefit from DOC treatment. DOC‐resistant PC3‐DR and DU145‐DR sublines and their sensitive parental cell lines (DU145, PC3) were comparatively analyzed using liquid chromatography‐coupled tandem mass spectrometry (LC‐MS/MS). Results were filtered using bioinformatics approaches to identify promising serum biomarkers. Serum levels of five proteins were determined in serum samples of 66 DOC‐treated metastatic castration‐resistant PC patients (mCRPC) using ELISA. Results were correlated with clinicopathological and survival data. CD44 was subjected to further functional cell culture analyses. We found at least 177 two‐fold significantly overexpressed proteins in DOC‐resistant cell lines. Our bioinformatics method suggested 11/177 proteins to be secreted into the serum. We determined serum levels of five (CD44, MET, GSN, IL13RA2 and LNPEP) proteins in serum samples of DOC‐treated patients and found high CD44 serum levels to be independently associated with poor overall survival (p = 0.001). In accordance, silencing of CD44 in DU145‐DR cells resulted in re‐sensitization to DOC. In conclusion, high serum CD44 levels may help identify DOC‐resistant patients and may thereby help optimize clinical decision‐making regarding type and timing of therapy for mCRPC patients. In addition, our in vitro results imply the possible functional involvement of CD44 in DOC resistance. [ABSTRACT FROM AUTHOR]

Objective: We aimed to study the expressions of miR-103a-3p and TRIM66 in prostate cancer (PCa) cells, explore the direct target genes of miR-103a-3p, and analyze the effects of miR-103a-3p targeted regulation of the TRIM66 axis on docetaxel (DTX) resistance and glycolysis of PCa cells. Methods: Human normal prostate cells and PCa cells were used to detect the expressions of miR-103a-3p and TRIM66 and analyze their relationship. DTX-resistant (DR) PCa cells were established and transfected with miR-103a-3p and TRIM66 plasmids. The MTT assay, the plate cloning assay, the wound healing assay, and the Transwell assay were used to detect cell viability, colony formation, cell migration, and cell invasion, respectively. Cell glycolysis was analyzed using a cell glycolysis kit. Results: The expression of miR-103a-3p was low and that of TRIM66 was high in PCa cells. MiR-103a-3p had a binding site with TRIM66, and the double luciferase report confirmed that they had a targeting relationship. Compared with the PCa group cells, the DTX-resistant group cells showed increased resistance to DTX. The resistance index was 13.33, and the doubling time of the DTX-resistant group cells was significantly longer than that of the PCa group cells. The DTX-resistant group showed more obvious low expression of miR-103a-3p and high expression of TRIM66. After the DTX-resistant group cells were transfected with miR-103a-3p and TRIM66 plasmids, the expression of miR-103a-3p increased significantly and that of TRIM66 decreased significantly. Upregulation of miR-103a-3p and interference with TRIM66 can inhibit the proliferation, metastasis, and glycolysis of DTX-resistant cells. Conclusion: The expression of miR-103a-3p was downregulated and that of TRIM66 was upregulated in the malignant progression of PCa, especially during DTX resistance. Upregulation of miR-103a-3p and interference with TRIM66 can inhibit DTX resistance and glycolysis of PCa cells. Targeting TRIM66 may provide potential application value in molecular therapy for PCa. [ABSTRACT FROM AUTHOR]

Several microRNAs (miRNAs) and circular RNAs (circRNAs) were reported to be involved in the Docetaxel (DTX) chemoresistance of cancer treatment, but the underlying mechanisms remain to be explored. In this study, we established cellular and animal models respectively to study the effect and underlying molecular mechanisms of the dysregulation of circRNA_0006404 and circRNA_0000735 in tumor response to DTX treatment. Quantitative real-time PCR was performed to measure the expression of circRNA_0006404, miR-346, circRNA_0000735, miR-526b, Dickkopf-related protein 3 (DKK3), and Dickkopf-related protein 4 (DKK4) mRNA. The expression of circRNA_0006404 and circRNA_0000735 was remarkably suppressed and activated in DTX-treated SKOV3-R cell lines, respectively. As revealed by luciferase assays, circRNA_0006404 and circRNA_0000735 was found to be respectively targeted by miR-346 and miR-526b, while DKK3 and DKK4 were respectively targeted by miR-346 and miR-526b. Moreover, the expression of DKK3 and DKK4, which were targets of miR-346 and miR-526b, respectively, was significantly altered along with the expression of p-GP. Furthermore, circ_0006404 shRNA and circRNA_0000735 shRNA showed remarkable efficiency in stimulating the expression of circRNA_0006404, miR-346, DKK3, circRNA_0000735, miR-526b, DKK4, and p-GP in cellular and animal models. Accordingly, the cell apoptosis and proliferation were apparently changed by circ_0006404 shRNA and circRNA_0000735 shRNA in both cellular and animal models. In summary, our study found the involvement of the circRNA_0006404/miR-346/DKK3/p-GP and circRNA_0000735/miR-546b/DKK4/p-GP axis in the tumor response to DTX. Both the up-regulation of circRNA_0006404 and down-regulation of circRNA_0000735 could inhibit the expression of p-GP in vivo and ex vivo, leading to the suppressed tumor response to DTX treatment. [ABSTRACT FROM AUTHOR]

As treatment options for patients with incurable metastatic castration‐resistant prostate cancer (mCRPC) are considerably limited, novel effective therapeutic options are needed. Checkpoint kinase 1 (CHK1) is a highly conserved protein kinase implicated in the DNA damage response (DDR) pathway that prevents the accumulation of DNA damage and controls regular genome duplication. CHK1 has been associated with prostate cancer (PCa) induction, progression, and lethality; hence, CHK1 inhibitors SCH900776 (also known as MK‐8776) and the more effective SCH900776 analog MU380 may have clinical applications in the therapy of PCa. Synergistic induction of DNA damage with CHK1 inhibition represents a promising therapeutic approach that has been tested in many types of malignancies, but not in chemoresistant mCRPC. Here, we report that such therapeutic approach may be exploited using the synergistic action of the antimetabolite gemcitabine (GEM) and CHK1 inhibitors SCH900776 and MU380 in docetaxel‐resistant (DR) mCRPC. Given the results, both CHK1 inhibitors significantly potentiated the sensitivity to GEM in a panel of chemo‐naïve and matched DR PCa cell lines under 2D conditions. MU380 exhibited a stronger synergistic effect with GEM than clinical candidate SCH900776. MU380 alone or in combination with GEM significantly reduced spheroid size and increased apoptosis in all patient‐derived xenograft 3D cultures, with a higher impact in DR models. Combined treatment induced premature mitosis from G1 phase resulting in the mitotic catastrophe as a prestage of apoptosis. Finally, treatment by MU380 alone, or in combination with GEM, significantly inhibited tumor growth of both PC339‐DOC and PC346C‐DOC xenograft models in mice. Taken together, our data suggest that metabolically robust and selective CHK1 inhibitor MU380 can bypass docetaxel resistance and improve the effectiveness of GEM in DR mCRPC models. This approach might allow for dose reduction of GEM and thereby minimize undesired toxicity and may represent a therapeutic option for patients with incurable DR mCRPC.

Abstract Background Prostate cancer stem-like cells (PCSCs) likely participate in tumor progression and recurrence and demonstrate resistance to chemotherapy. The Notch pathway plays a role in the maintenance of the stemness in PCSCs. This study aimed to investigate the efficacy of Notch signaling inhibition as an adjuvant to docetaxel (DOX) in PCSCs. Methods PCSCs derived from the PC-3 cell line were examined for Notch-1 expression. The effect of Notch inhibition on response to DOX was evaluated in PCSCs in vitro and in murine models using a γ-secretase inhibitor (GSI), PF-03084014. Impacts on cell proliferation, apoptosis, cell cycle, and sphere formation were evaluated. Results PC-3 PCSCs expressed elevated Notch-1 mRNA compared with PC-3 parental cells. The combination of GSI with DOX promoted DOX-induced cell growth inhibition, apoptosis, cell cycle arrest, and sphere formation in PCSCs. In nude mice bearing PC-3 PCSC-derived tumors, the combination of GSI and DOX reduced the tumor growth, which was associated with the decreased Notch-1 expression in tumor tissues. Conclusions These results reveal that inhibition of the Notch pathway enhances the anti-tumor effect of DOX in PC-3 PCSCs, and suggest that Notch inhibition may have clinical benefits in targeting PCSCs.

Objective: We aimed to study the expressions of miR-103a-3p and TRIM66 in prostate cancer (PCa) cells, explore the direct target genes of miR-103a-3p, and analyze the effects of miR-103a-3p targeted regulation of the TRIM66 axis on docetaxel (DTX) resistance and glycolysis of PCa cells.Methods: Human normal prostate cells and PCa cells were used to detect the expressions of miR-103a-3p and TRIM66 and analyze their relationship. DTX-resistant (DR) PCa cells were established and transfected with miR-103a-3p and TRIM66 plasmids. The MTT assay, the plate cloning assay, the wound healing assay, and the Transwell assay were used to detect cell viability, colony formation, cell migration, and cell invasion, respectively. Cell glycolysis was analyzed using a cell glycolysis kit.Results: The expression of miR-103a-3p was low and that of TRIM66 was high in PCa cells. MiR-103a-3p had a binding site with TRIM66, and the double luciferase report confirmed that they had a targeting relationship. Compared with the PCa group cells, the DTX-resistant group cells showed increased resistance to DTX. The resistance index was 13.33, and the doubling time of the DTX-resistant group cells was significantly longer than that of the PCa group cells. The DTX-resistant group showed more obvious low expression of miR-103a-3p and high expression of TRIM66. After the DTX-resistant group cells were transfected with miR-103a-3p and TRIM66 plasmids, the expression of miR-103a-3p increased significantly and that of TRIM66 decreased significantly. Upregulation of miR-103a-3p and interference with TRIM66 can inhibit the proliferation, metastasis, and glycolysis of DTX-resistant cells.Conclusion: The expression of miR-103a-3p was downregulated and that of TRIM66 was upregulated in the malignant progression of PCa, especially during DTX resistance. Upregulation of miR-103a-3p and interference with TRIM66 can inhibit DTX resistance and glycolysis of PCa cells. Targeting TRIM66 may provide potential application value in molecular therapy for PCa.

Prostate cancer (PCa), a prevalent malignancy worldwide, is frequently identified in advanced stages due to the absence of distinctive early symptoms, thereby culminating in the development of chemotherapy-induced drug resistance. Exploring novel resistance mechanisms and identifying new therapeutic agents can facilitate the advancement of more efficacious strategies for PCa treatment. Bioinformatics analysis was employed to investigate the expression of FOXG1 in PCa tissues. Subsequently, qRT-PCR was utilized to validate FOXG1 mRNA expression levels in corresponding PCa cell lines. FOXG1 knockdown was performed, and cell proliferation was assessed using CCK-8 assays, while cell migration and invasion capabilities were evaluated through wound healing and Transwell assays. Western blot and Seahorse analyzer were used to measure oxidative phosphorylation (OXPHOS) levels. Additionally, to explore potential approaches to alleviate PCa drug resistance, this study assessed the impact of biologically active saikosaponin-d (SSd) on PCa malignant progression and resistance by regulating FOXG1 expression. FOXG1 exhibited high expression in PCa tissues and cell lines. Knockdown of FOXG1 inhibited the proliferation, migration, and invasion of PCa cells, while FOXG1 overexpression had the opposite effect and promoted OXPHOS levels. The addition of an OXPHOS inhibitor prevented this outcome. Finally, SSd was shown to suppress FOXG1 expression and reverse docetaxel resistance in PCa cells through the OXPHOS pathway. This work demonstrated that SSd mediated FOXG1 to reverse malignant progression and docetaxel resistance in PCa through OXPHOS. • FOXG1 exhibited high expression in PCa tissues and cell lines. • Knockdown of FOXG1 inhibited the proliferation, migration, invasion, and docetaxel resistance of PCa cells. • FOXG1 overexpression promotes docetaxel resistance in PCa through OXPHOS. • SSd was shown to suppress FOXG1 expression and reverse docetaxel resistance in PCa cells through the OXPHOS pathway. [ABSTRACT FROM AUTHOR]

To investigate the relationship between non-coding RNAs [especially circular RNAs (circRNAs)] and docetaxel resistance in breast cancer, and to find potential predictive biomarkers for taxane-containing therapies, we have performed transcriptome and microRNA (miRNA) sequencing for two established docetaxel-resistant breast cancer (DRBC) cell lines and their docetaxel-sensitive parental cell lines. Our analyses revealed differences between circRNA signatures in the docetaxel-resistant and -sensitive breast cancer cells, and discovered circRNAs generated by multidrug-resistance genes in taxane-resistant cancer cells. In DRBC cells, circABCB1 was identified and validated as a circRNA that is strongly up-regulated, whereas circEPHA3.1 and circEPHA3.2 are strongly down-regulated. Furthermore, we investigated the potential functions of these circRNAs by bioinformatics analysis, and miRNA analysis was performed to uncover potential interactions between circRNAs and miRNAs. Our data showed that circABCB1, circEPHA3.1 and circEPHA3.2 may sponge up eight significantly differentially expressed miRNAs that are associated with chemotherapy and contribute to docetaxel resistance via the PI3K-Akt and AGE-RAGE signaling pathways. We also integrated differential expression data of mRNA, long non-coding RNA, circRNA, and miRNA to gain a global profile of multi-level RNA changes in DRBC cells, and compared them with changes in DNA copy numbers in the same cell lines. We found that Chromosome 7 q21.12-q21.2 was a common region dominated by multi-level RNA overexpression and DNA amplification, indicating that overexpression of the RNA molecules transcribed from this region may result from DNA amplification during stepwise exposure to docetaxel. These findings may help to further our understanding of the mechanisms underlying docetaxel resistance in breast cancer.

To investigate the relationship between non-coding RNAs [especially circular RNAs (circRNAs)] and docetaxel resistance in breast cancer, and to find potential predictive biomarkers for taxane-containing therapies, we have performed transcriptome and microRNA (miRNA) sequencing for two established docetaxel-resistant breast cancer (DRBC) cell lines and their docetaxel-sensitive parental cell lines. Our analyses revealed differences between circRNA signatures in the docetaxel-resistant and -sensitive breast cancer cells, and discovered circRNAs generated by multidrug-resistance genes in taxane-resistant cancer cells. In DRBC cells, circABCB1 was identified and validated as a circRNA that is strongly up-regulated, whereas circEPHA3.1 and circEPHA3.2 are strongly down-regulated. Furthermore, we investigated the potential functions of these circRNAs by bioinformatics analysis, and miRNA analysis was performed to uncover potential interactions between circRNAs and miRNAs. Our data showed that circABCB1, circEPHA3.1 and circEPHA3.2 may sponge up eight significantly differentially expressed miRNAs that are associated with chemotherapy and contribute to docetaxel resistance via the PI3K-Akt and AGE-RAGE signaling pathways. We also integrated differential expression data of mRNA, long non-coding RNA, circRNA, and miRNA to gain a global profile of multi-level RNA changes in DRBC cells, and compared them with changes in DNA copy numbers in the same cell lines. We found that Chromosome 7 q21.12-q21.2 was a common region dominated by multi-level RNA overexpression and DNA amplification, indicating that overexpression of the RNA molecules transcribed from this region may result from DNA amplification during stepwise exposure to docetaxel. These findings may help to further our understanding of the mechanisms underlying docetaxel resistance in breast cancer. [ABSTRACT FROM AUTHOR]

Docetaxel is a major treatment for advanced prostate cancer (PCa); however, its resistance compromises clinical effectiveness. Estrogen receptor-related receptor alpha (ERRα) belongs to an orphan nuclear receptor superfamily and was recently found to be closely involved in cancer. In the present study, we found that ERRα was involved in docetaxel resistance in PCa. Overexpression of ERRα conferred docetaxel resistance in PCa cell lines, and cells with ERRα downregulation were more sensitive to docetaxel. Among the drug resistance-related genes, ABCC4 demonstrated synchronous expression after ERRα manipulation in cells. Moreover, both ERRα and ABCC4 were overexpressed in the docetaxel-resistant cell, which could be reversed by ERRα knockdown. The knockdown of ERRα also reversed the reduced drug accumulation in the docetaxel-resistant cell. We also demonstrated for the first time that ABCC4 was a direct target of ERRα as determined by the CHIP and luciferase assays. Bioinformatics analysis revealed high expression of ERRα and ABCC4 in PCa patients, and a number of potential ERRα/ABCC4 targets were predicted. In conclusion, our study demonstrated a critical role for ERRα in docetaxel resistance by directly targeting ABCC4 and stressed the importance of ERRα as a potential therapeutic target for drug-resistant PCa.

Docetaxel (DOC) is the most important chemotherapeutic drug for the treatment of triple negative breast cancer (TNBC); however, acquired drug resistance upon the long-term treatment limits its therapeutic effect. Maslinic acid (MA), a natural triterpene from Olea europaea L., attracts increasing interest in recent years because of its promising anti-cancer activity, but the reversal effect of MA on drug resistance in cancer therapy is rarely explored. In this study, the combined effect of DOC and MA on human docetaxel-resistant triple negative breast carcinoma MDA-MB-231 (MDA-MB-231/DOC) cells was investigated. The enhanced effect of MA on DOC cytotoxicity and DOC accumulation was assessed by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay and HPLC (high performance liquid chromatography) analysis in MDA-MB-231/DOC cells. Western blot, co-immunoprecipitation assay, luciferase reporter assay, and chromatin immunoprecipitation (ChIP) assay were performed for exploring the underlying mechanisms. Our data indicated that the co-treatment of MA could dose-dependently enhance DOC sensitivity and cellular DOC accumulation in MDA-MB-231/DOC cells. Moreover, MELK-FoxM1-ABCB1 signaling cascade was confirmed to contribute to DOC resistance in MDA-MB-231/DOC cells. In such process, MA directly suppressed expressions and interaction of MELK and FoxM1 as well as the transcriptional activity of FoxM1, and thus reducing the expression of ABCB1. Overall, our study suggests that the combined use of DOC and MA may be helpful for overcoming DOC resistance in human TNBC therapy.

Background: Mesenchymal stem cells (MSCs) have been proved to drive castration resistant prostate cancer (CRPC). In this study, we aim to investigate the contribution of MSCs to the development of docetaxel resistance in CRPC cells and its potential mechanisms. Methods: The effect of MSCs on CRPC cells resistance to docetaxel was determined using in vivo and in vitro approaches. CCK8 and PI/Annexin V-FITC assay were used to examined the cell viability and apoptosis. The concentration of transforming growth factor-β1 was measured by enzyme-linked immunosorbent assay and small interfering RNA was used for functional analyses. Results: MSCs significantly reduced the sensitivity of CRPC cells to docetaxel-induced proliferation inhibition and apoptosis promotion in vivo and in vitro. CRPC cells cocultured with MSCs under docetaxel administration have an increased autophagy activation, while autophagy inhibitor could effectively reversed MSCs-induced resistance to docetaxel. Additionally, MSCs-induced CRPC cell autophagy increase under docetaxel administration depends on MSCs secreting TGF-β1 and inhibition of TGF-β1 secretion in MSCs could consequently increase the sensitivity of CRPC cells to docetaxel. Conclusions: These results suggest that docetaxel administrated CRPC cells may elicit MSCs secreting TGF-β1 increase, which desensitizes CRPC to docetaxel chemotherapy accelerating chemoresistance occurrence via inducing cell autophagy. [ABSTRACT FROM AUTHOR]

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As treatment options for patients with incurable metastatic castration‐resistant prostate cancer (mCRPC) are considerably limited, novel effective therapeutic options are needed. Checkpoint kinase 1 (CHK1) is a highly conserved protein kinase implicated in the DNA damage response (DDR) pathway that prevents the accumulation of DNA damage and controls regular genome duplication. CHK1 has been associated with prostate cancer (PCa) induction, progression, and lethality; hence, CHK1 inhibitors SCH900776 (also known as MK‐8776) and the more effective SCH900776 analog MU380 may have clinical applications in the therapy of PCa. Synergistic induction of DNA damage with CHK1 inhibition represents a promising therapeutic approach that has been tested in many types of malignancies, but not in chemoresistant mCRPC. Here, we report that such therapeutic approach may be exploited using the synergistic action of the antimetabolite gemcitabine (GEM) and CHK1 inhibitors SCH900776 and MU380 in docetaxel‐resistant (DR) mCRPC. Given the results, both CHK1 inhibitors significantly potentiated the sensitivity to GEM in a panel of chemo‐naïve and matched DR PCa cell lines under 2D conditions. MU380 exhibited a stronger synergistic effect with GEM than clinical candidate SCH900776. MU380 alone or in combination with GEM significantly reduced spheroid size and increased apoptosis in all patient‐derived xenograft 3D cultures, with a higher impact in DR models. Combined treatment induced premature mitosis from G1 phase resulting in the mitotic catastrophe as a prestage of apoptosis. Finally, treatment by MU380 alone, or in combination with GEM, significantly inhibited tumor growth of both PC339‐DOC and PC346C‐DOC xenograft models in mice. Taken together, our data suggest that metabolically robust and selective CHK1 inhibitor MU380 can bypass docetaxel resistance and improve the effectiveness of GEM in DR mCRPC models. This approach might allow for dose reduction of GEM and thereby minimize undesired toxicity and may represent a therapeutic option for patients with incurable DR mCRPC. [ABSTRACT FROM AUTHOR]

Docetaxel is a major treatment for advanced prostate cancer (PCa); however, its resistance compromises clinical effectiveness. Estrogen receptor-related receptor alpha (ERRα) belongs to an orphan nuclear receptor superfamily and was recently found to be closely involved in cancer. In the present study, we found that ERRα was involved in docetaxel resistance in PCa. Overexpression of ERRα conferred docetaxel resistance in PCa cell lines, and cells with ERRα downregulation were more sensitive to docetaxel. Among the drug resistance-related genes, ABCC4 demonstrated synchronous expression after ERRα manipulation in cells. Moreover, both ERRα and ABCC4 were overexpressed in the docetaxel-resistant cell, which could be reversed by ERRα knockdown. The knockdown of ERRα also reversed the reduced drug accumulation in the docetaxel-resistant cell. We also demonstrated for the first time that ABCC4 was a direct target of ERRα as determined by the CHIP and luciferase assays. Bioinformatics analysis revealed high expression of ERRα and ABCC4 in PCa patients, and a number of potential ERRα/ABCC4 targets were predicted. In conclusion, our study demonstrated a critical role for ERRα in docetaxel resistance by directly targeting ABCC4 and stressed the importance of ERRα as a potential therapeutic target for drug-resistant PCa. [ABSTRACT FROM AUTHOR]