Docetaxel In Prostate Cancer Research Articles

Genetic Test Predicts Survival Benefit From Docetaxel in Prostate Cancer

Genetic Test Predicts Survival Benefit From Docetaxel in Prostate Cancer

Fucoidan Inhibits Prostate Cancer Growth Through Modulation of Different Cell Deaths.

Docetaxel (DOC) is the main chemotherapeutic agent for the treatment of advanced metastatic prostate cancer. Docetaxel shows anticancer effects by preventing the depolymerization of microtubules in the cell, therefore preventing cell division. However, the low survival effect of docetaxel has prompted researchers to search for novel therapeutic agents. Fucoidan (FUC) is a sulfated polysaccharide derived from brown algae. It has many bioactivities which makes fucoidan a promising anticancer agent. In this study, the potential anti-tumorigenic and preventive effects of fucoidan with or without docetaxel in prostate cancer were investigated by analyzing different cell death modalities. The in-vivo six groups (n = 8) were conducted; preventive (Pt), docetaxel treated after preventive (Pt-D), control, fucoidan (FUC), docetaxel (DOC), and FUC and DOC (FUC+DOC) combination. Apoptotic, necroptotic, and autophagic cell death-related protein expressions were assessed in tumor tissues by using immunohistochemical staining. Oxidative stress-related lipid peroxidation, glutathione peroxidase, and glutathione levels were also determined in tumor tissues. Although apoptotic, necroptotic, and autophagic cell deaths were significantly induced in agent-treated groups compared to the control. Apoptotic cell death was more significantly induced in FUC and FUC+DOC-treated groups. Necroptotic cell death was increased considerably by inducing MLKL protein expression in all treatment groups. In the FUC, Pt, and DOC groups, LC3A/B expressions were significantly increased. DOC, FUC+DOC, and Pt-D treatments caused a significant increase in Beclin-1 expression. Oxidative stress-related MDA, GPX, and GSH levels significantly decreased with FUC treatment. The anti-tumorigenic effects of FUC and DOC were also demonstrated through tumor size reduction. According to the findings of this study, FUC inhibited tumor growth temporally and dimensionally, especially in preventive applications. FUC and FUC+DOC combinations in both treatment groups showed anti-tumorigenic effects. The results of this study suggest that fucoidan is a promising anticancer agent against prostate cancer. FUC can be considered as a preventive or treatment agent in prostate cancer therapy with DOC. Further studies are needed to fully elucidate the mechanism of action of fucoidan in metastatic prostate cancer.

Single-cell deconvolution algorithms analysis unveils autocrine IL11-mediated resistance to docetaxel in prostate cancer via activation of the JAK1/STAT4 pathway

BackgroundDocetaxel 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.MethodsSingle-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.ResultsAutocrine 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.ConclusionOur 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

Cholinergic signaling via muscarinic M1 receptor confers resistance to docetaxel in prostate cancer

Docetaxel is the most commonly used chemotherapy for advanced prostate cancer (PC), including castration-resistant disease (CRPC), but the eventual development of docetaxel resistance constitutes a major clinical challenge. Here, we demonstrate activation of the cholinergic muscarinic M1 receptor (CHRM1) in CRPC cells upon acquiring resistance to docetaxel, which is manifested in tumor tissues from PC patients post- vs. pre-docetaxel. Genetic and pharmacological inactivation of CHRM1 restores the efficacy of docetaxel in resistant cells. Mechanistically, CHRM1, via its first and third extracellular loops, interacts with the SEMA domain of cMET and forms a heteroreceptor complex with cMET, stimulating a downstream mitogen-activated protein polykinase program to confer docetaxel resistance. Dicyclomine, a clinically available CHRM1-selective antagonist, reverts resistance and restricts the growth of multiple docetaxel-resistant CRPC cell lines and patient-derived xenografts. Our study reveals a CHRM1-dictated mechanism for docetaxel resistance and identifies a CHRM1-targeted combinatorial strategy for overcoming docetaxel resistance in PC.

LDH-A Inhibitor as a Remedy to Potentiate the Anticancer Effect of Docetaxel in Prostate Cancer.

Increased LDH-A activity promotes tumor growth, migration, invasion, and metastasis. This study aimed to investigate the effects of the combination of LDH-A inhibitor and Docetaxel on apoptosis and epithelial-mesenchymal transition (EMT) in the murine prostate cancer (PCa) model. The prostate cancer murine model was developed subcutaneously in 50 male B57CL/6 mice using the Tramp-C2 prostate cancer cell line. From the tumor tissue samples, apoptosis analysis was performed using TUNEL staining, and EMT was investigated using western blot and qPCR. Hematoxylin-eosin staining (HE) and Periodic acid-Schiff staining were used to histopathologically examine liver and kidney tissues. Lactate levels revealed that the Warburg effect was reversed with the LDH-A inhibitor. Both serum and tumor tissue apoptosis increased, and tumor sizes reduced in PCa+LDH-A inhibitor + Docetaxel treatment groups (p<0.05). The combination of LDH-A inhibitor and Docetaxel inhibited EMT mechanism by causing a decrease in Snail, Slug, Twist, and HIF-1α expressions as well as a decrease in N-cadherin and an increase in E-cadherin levels. Reprogramming glucose metabolism with an LDH-A inhibitor can increase the effectiveness of Docetaxel on apoptosis and metastasis mechanisms in PCa.

Non-Coding RNAs and the Development of Chemoresistance to Docetaxel in Prostate Cancer: Regulatory Interactions and Approaches Based on Machine Learning Methods.

Chemotherapy based on taxane-class drugs is the gold standard for treating advanced stages of various oncological diseases. However, despite the favorable response trends, most patients eventually develop resistance to this therapy. Drug resistance is the result of a combination of different events in the tumor cells under the influence of the drug, a comprehensive understanding of which has yet to be determined. In this review, we examine the role of the major classes of non-coding RNAs in the development of chemoresistance in the case of prostate cancer, one of the most common and socially significant types of cancer in men worldwide. We will focus on recent findings from experimental studies regarding the prognostic potential of the identified non-coding RNAs. Additionally, we will explore novel approaches based on machine learning to study these regulatory molecules, including their role in the development of drug resistance.

UP11 - WITHDRAWN: A polymer-based nano-delivery system for tumor-targeted delivery of Docetaxel in prostate cancer

UP11 - WITHDRAWN: A polymer-based nano-delivery system for tumor-targeted delivery of Docetaxel in prostate cancer

Ferroptosis Induction Improves the Sensitivity of Docetaxel in Prostate Cancer.

Docetaxel resistance seriously affects its clinical application in prostate cancer (PCa). Ferroptosis is a type of iron-dependent cell death driven by lipid peroxidation. It has been recently found that ferroptosis influences various biological processes. However, the potential role of ferroptosis in docetaxel chemotherapy for PCa is still elusive. In this study, we aimed to explore whether altering the level of ferroptosis can affect docetaxel sensitivity in PCa. The results indicated that docetaxel promoted ferroptotic cell death in several PCa cells, and ferroptosis inducers, erastin, and RSL3 markedly increased the cytotoxic effect of docetaxel. Furthermore, our results showed that ferroptosis resistance was closely associated with docetaxel insensitivity in PCa-resistant cells. Erastin or RSL3 rendered resistant PCa cells susceptible to docetaxel, with elevated levels of lipid ROS and decreased protein expression of GPX4 and SLC7A11. Moreover, treatment with erastin and RSL3 led to significant suppression of resistant tumors, and the combination of RSL3 with docetaxel significantly halted tumor growth in vivo when compared with either drug. Taken together, our findings indicate that ferroptosis is involved in docetaxel resistance, and its inducers are promising therapeutic strategies for advanced PCa.

Oncolytic Adenovirus with SPAG9 shRNA Driven by DD3 Promoter Improved the Efficacy of Docetaxil for Prostate Cancer.

Prostate cancer (PCa) is a common malignant tumor of the male urinary system and ranks the second in the causes of tumor-related deaths. Differential display code 3 (DD3) is a noncoding gene that is specifically expressed in PCa. High expression of sperm-associated antigen 9 (SPAG9) is closely related to tumorigenesis of PCa, and SPAG9 is a therapeutic target for PCa. In this study, a new oncolytic adenovirus DD3-ZD55-SPAG9 was constructed by using DD3 promoter to enhance the efficacy and safety of adenovirus. The combined use of DD3-ZD55-SPAG9 and docetaxel showed that DD3-ZD55-SPAG9 significantly improved the anti-tumor efficacy of docetaxel in PCa both in vitro and in vivo. The mechanism was related to the induction of tumor cell apoptosis and the inhibition of tumor cell invasion. In conclusion, DD3-ZD55-SPAG9 combined with docetaxel is an effective strategy for PCa therapy.

Differential effect of body mass index (BMI) on outcomes of patients treated with docetaxel in prostate cancer - An exploratory analysis.

Objective: There are contradictory data on differential effect of docetaxel based on BMI in patients with breast and prostate cancer. We performed an exploratory analysis to determine if the benefit of docetaxel in patients with metastatic castration-resistant prostate cancer (mCRPC) is modified by BMI. Methods: We performed a post hoc analysis of the data retrieved from the ENTHUSE M1C study. BMI (kg/m2) was categorized as: 18.5 to <25 as lean; 25 to <30 as overweight; and ≥30 as obese. Cox regression models were constructed to determine the impact of BMI on progression-free survival (PFS) and overall survival (OS). Results: A total of 466 patients were eligible for the current analysis. The median PFS was 7.3, 7.7 and 8.4 months (hazard ratio [HR], 0.92; 95% confidence interval [CI], 0.81 to 1.06; P = 0.261) in lean, overweight and obese patients. The median OS was 16.6, 20.1 and 21.4 months (HR, 0.75; 95% CI, 0.63 to 0.89; P = 0.002) for lean, overweight and obese patients. After adjusting for baseline and tumor characteristics, there was no association of BMI with PFS (overweight, HR, 0.89; 95% CI, 0.71 to 1.13; P = 0.353; obese, HR, 0.86; 95% CI, 0.66 to 1.13; P = 0.277) while overweight (HR, 0.68; 95% CI, 0.51 to 0.89; P = 0.006) and obese (HR, 0.59; 95% CI, 0.41 to 0.83; P = 0.003) patients had significantly better OS compared with lean patients. Conclusions: There was no effect of BMI on PFS in patients with mCRPC receiving docetaxel. Interestingly, overweight and obese patients had a longer OS compared with lean patients, which is in contradiction to a recent study in breast cancer; and warrants further investigation.

Long non-coding RNA PCDRlnc1 confers docetaxel resistance in prostate cancer by promoting autophagy.

Docetaxel resistance seriously affects its clinical application in prostate cancer (PCa). Long noncoding RNAs (lncRNAs) influence the chemosensitivity of various cancers. However, the potential involvement of lncRNAs in docetaxel sensitivity remains largely unknown in PCa. In the present study, we used RNA sequencing to compare the expression profiles of lncRNAs in docetaxel-resistant PCa cells and their parental cells and identified a novel lncRNA, ENSG00000234147, termed as PCa docetaxel resistance-associated lncRNA1 (PCDRlnc1). Our results indicated that PCDRlnc1 is closely associated with docetaxel resistance in PCa, and PCDRlnc1 knockout markedly sensitized the resistant cells to docetaxel in vitro and in vivo. In addition, PCDRlnc1 inhibition markedly suppressed docetaxel-induced autophagy. Conversely, PCDRlnc1 overexpression promoted autophagy. Mechanistically, PCDRlnc1 interacted with UHRF1 (ubiquitin-like with plant homeodomain and ring finger domains 1) and promoted its transcription level in PCa cells, leading to the activation of autophagic Beclin-1 signaling. Together, our data demonstrate that PCDRlnc1 is a novel key regulator of PCa docetaxel resistance, suggesting that it may be used as a potential biomarker of docetaxel resistance and therapeutic target in PCa.

A phase II study to evaluate the effects of docetaxel plus lycopene in advanced castrate-resistant prostate cancer.

77 Background: Lycopene, the carotenoid responsible for the red colors seen in tomatoes, grapefruit, and other foods, has demonstrated synergism with docetaxel in prostate cancer cell culture and tumor xenograft models. This phase II study investigated the clinical activity and safety profile of docetaxel plus lycopene in advanced castrate resistant prostate cancer. Methods: Eligible patients had histologically confirmed adenocarcinoma of the prostate, two rising pre-study prostate specific antigen (PSA) values ≥ 1 ng/ml, and no prior treatment with any chemotherapy, biological therapy, or investigational drug. All patients initially received docetaxel 75mg/m2 every 21 days in combination with lycopene 30 mg orally once daily. The primary endpoint was PSA response rate, defined as the proportion of subjects achieving a ≥ 50% reduction in PSA at any point after starting therapy. Secondary endpoints included median time to PSA progression, duration of response (DOR), and overall survival (OS). Results: Fourteen patients were screened, and thirteen patients were initiated on protocol therapy. Median age was 77 years (range 55-90). Twelve patients (92%) had bone metastases. Four patients (30%) had bone and visceral metastases. The PSA response rate was 76.9% [95% confidence interval (CI), 46.2-94.9], comprising of ten PSA responses. Two patients had a best response of stable disease, yielding a disease control rate of 92% [95% CI, 57.2-98.2]. Median time to PSA progression was 8 months [95% CI, 3.5-8.7]. Median duration of response was 7.3 months [95% CI, 4.8-13.2]. On 5-year follow-up, median overall survival was 35.1 months [95% CI, 25.7-57.7]. The most frequently reported ( &gt; 15%) non-hematologic adverse events included diarrhea, nausea, vomiting, peripheral neuropathy, weight loss, fatigue, onycholysis, and alopecia. One patient (7%) experienced febrile neutropenia. No patients experienced grade 3 or above anemia. Conclusions: The combination of docetaxel with lycopene led to improved PSA response rate and tolerability in patients with advanced castrate resistant prostate cancer. Docetaxel plus lycopene merits further research in this patient population. Clinical trial information: NCT01882985.

Differential effect of body mass index (BMI) on outcomes of patients treated with docetaxel in prostate cancer: An exploratory analysis.

129 Background: Docetaxel is a lipophilic drugs with a high affinity for adipose tissue resulting in a higher volume of distribution.There are contradictory data with regards to the differential effect of docetaxel based on BMI in breast cancer patients. However, there are no such data in patients with prostate cancer. A We performed an exploratory analysis to determine if the benefit of docetaxel in patients with metastatic castration resistant prostate cancer (mCRPC) is modified by BMI. Methods: This is a post hoc analysis of data retrieved from the phase III ENTHUSE M1C study that assessed the efficacy and safety of additional zibotentan in combination with docetaxel in patients with mCRPC (ClinicalTrials.gov identifier: NCT00617669). BMI (kg/m2) was categorized as: 18.5 to &lt; 25, lean; 25 to &lt; 30, overweight; and ≥ 30, obese. Cox regression models were constructed to determine the impact of BMI on progression-free survival (PFS) and overall survival (OS) after adjusting for baseline characteristics. Results: A total of 466 patients were eligible for current analysis, of whom 34%, 46% and 20% were &lt; 65 years, 65-74 years and &gt; 75 years, respectively. The median total and free baseline PSA were 99.5 (interquartile range [IQR], 33.6 to 237.0) ng/mL and 13.9 (IQR, 5.4 to 37.4) ng/mL, respectively. There were 31% (n = 145), 46% (n = 213) and 23% (n = 108) lean, overweight and obese patients. Visceral metastasis was present in 52% patients, while the number of bone metastases were 1-3 in 15%, 4 in 5%, 5-20 in 58% and ≥ 21 in 23%. The median number of cycles of docetaxel administered were 10 (IQR, 6-10). The median PFS was 7.3, 7.7 and 8.4 months (hazard ratio [HR], 0.92; 95% confidence interval [CI], 0.81 to 1.06; P = .26) for lean, overweight and obese patients, respectively. The median OS was 10.3, 10.7 and 12.4 months (HR, 0.75; 95% CI, 0.63 to 0.89; P = .01) for lean, overweight and obese patients, respectively. After adjusting for baseline and tumor related characteristics, there was no association of BMI with PFS (overweight, HR, 0.92; 95% CI, 0.73 to 1.17; P = .50; obese, HR, 0.90; 95% CI, 0.67 to 1.18; P = .42) while overweight (HR, 0.68; 95% CI, 0.52 to 0.91; P = .01) and obese (HR, 0.61; 95% CI, 0.43 to 0.88; P = .01) patients had significantly better OS as compared with lean patients. Conclusions: The differential effect of docetaxel based on BMI was not observed in patients with mCRPC. Interestingly, obese patients had a significantly longer OS, which warrants further investigation.

Glutamate-urea-based PSMA-targeted PLGA nanoparticles for prostate cancer delivery of docetaxel

Targeted drug delivery is a tool to make treatment more specific, selective, and effective and to prevent unwanted complications. Prostate specific membrane antigen (PSMA) is a useful biomarker in order to monitor and control prostate cancer. Glutamate-Urea-R (Glu-Urea-R) is a PSMA enzyme inhibitor capable of binding to this surface marker of prostate cancer cell in an efficient and special manner. The aim of this project was to develop a docetaxel-loaded nanoparticle of poly (lactic-co-glycolic acid) polyethylene glycol which is cojugated to a urea-based anti-PSMA ligand named glutamate-urea-lysine (glu-urea-lys) for targeted delivery of docetaxel in prostate cancer. The obtained nanoparticles, prepared by nanoprecipitation method, were spheres with a particle size of around 150 nm and zeta potential of −7.08 mV. Uptake studies on the PC3 (as PSMA negative) and LNCaP (as PSMA positive) cells demonstrated that drug uptake was efficient by the PSMA positive cells. IC50 of targeted NPs on LNCaP cell line compared to non-targeted ones was reduced by more than 70% in three different incubation times of 24, 48, and 72 h. In conclusion, the nanoparticles are expected to specifically transport docetaxel to PSMA-positive prostate cancer cells and consequently, enhance the antitumor efficacy of docetaxel on these cells.

CNTN-1 promotes docetaxel resistance and epithelial-to-mesenchymal transition via the PI3K/Akt signaling pathway in prostate cancer.

IntroductionTherapy options for prostate cancer (PCa) typically are centered on docetaxel-based chemotherapy but are limited by the effects of multi-drug resistance. Recent advances have illustrated a role of contactin-1 (CNTN-1) in tumor chemoresistance, while the function and mechanism of CNTN-1 in the resistance of docetaxel in prostate cancer have not yet been elucidated.Material and methodsDocetaxel (Dox)-resistant PCa cell lines of PC3 (PC3-DR) and DU145 (DU145-DR) were established, and short hairpin RNA (shRNA) constructs targeting CNTN-1 were generated to analyze the effect of knockdown of CNTN-1 on PCa progression. Cell Counting Kit-8 (CCK-8), flow cytometry, wound-healing, transwell and western blotting analysis were used to analyze cell proliferation, apoptosis, migration, invasion and related protein expression levels, respectively.ResultsKnockdown of CNTN-1 in PC3-DR and DU145-DR cells attenuated cell proliferation, migration, invasion, EMT phenotype, and drug resistance, and increased cell apoptosis further reduced the tumorigenic phenotype. Knockdown of CNTN-1 resulted in an anti-tumor effect in the xenograft tumor model, and decreased activity of the phosphoinositide 3-kinase (PI3K)/Akt signaling pathway both in vitro and in vivo.ConclusionsThe results of the present study suggest that downregulation of CNTN-1 may be an important mechanism to reverse chemoresistance in Dox-resistant PCa progression, thus shedding light on the development of novel anti-tumor therapeutics for the treatment of PCa.

Use of miR‑145 and testicular nuclear receptor 4 inhibition to reduce chemoresistance to docetaxel in prostate cancer.

The human testicular nuclear receptor 4 (TR4) is a critical regulatory gene for the progression of prostate cancer (PCa). Although it has been revealed that TR4 causes chemoresistance in PCa via the activation of octamer-binding transcription factor 4 (OCT4), the detailed mechanism remains unexplored. In the present study, it was revealed that inhibition of TR4 by shRNA in PCa enhanced the sensitivity to docetaxel in vitro and in vivo. TR4 induced the downregulation of miR-145 by directly binding it to the promoter of miR-145, which was confirmed by chromatin immunoprecipitation analysis and luciferase assay. The overexpression of miR-145 suppressed both the chemoresistance and the expression of OCT4 mRNA and protein. Additionally, the TR4 shRNA mediated re-sensitization to docetaxel, along with the downregulated expression of OCT4, were reversed by the concurrent inhibition of miR-145. The luciferase assay revealed that the activity of the wild-type OCT4 3′ untranslated region reporter was suppressed. This suppression diminished when the miR-145 response element mutated. These findings suggest an undescribed regulatory pathway in PCa, by which TR4 directly suppressed the expression of miR-145, thereby inhibiting its direct target OCT4, leading to the promotion of chemoresistance in PCa.

FOXM1 modulates docetaxel resistance in prostate cancer by regulating KIF20A

BackgroundDocetaxel resistance affects prognosis in advanced prostate cancer (PCa). The precise mechanisms remain unclear. Transcription factor Forkhead box M1 (FOXM1), which participates in cell proliferation and cell cycle progression, has been reported to affect the sensitivity of chemotherapy. This study explores the role of FOXM1 in PCa docetaxel resistance and its association with kinesin family member 20 A (KIF20A), which is known to promote therapeutic resistance in some cancers.MethodsWe monitored cell growth using MTT and colony formation assays, and cell apoptosis and cell cycle progression using flow cytometry. Wound-healing and transwell assays were used to detect cell invasion and migration. mRNA and protein expression were analyzed using quantitative reverse transcription polymerase chain reaction (qRT-PCR) and western blotting. We monitored FOXM1 binding to the KIF20A promoter using a ChIP assay. Tumorigenicity in nude mice was used to assess in vivo tumorigenicity.ResultsFOXM1 knockdown induced cell apoptosis and G2/M cell cycle arrest, suppressing cell migration and invasion in docetaxel-resistant PCa cell lines (DU145-DR and VCaP-DR). Exogenous FOXM1 overexpression was found in their parental cells. Specific FOXM1 inhibitor thiostrepton significantly weakened docetaxel resistance in vitro and in vivo. We also found that FOXM1 and KIF20A exhibited consistent and highly correlated overexpression in PCa cells and tissues. FOXM1 also regulated KIF20A expression at the transcriptional level by acting directly on a Forkhead response element (FHRE) in its promoter. KIF20A overexpression could partially reverse the effect on cell proliferation, cell cycle proteins (cyclinA2, cyclinD1 and cyclinE1) and apoptosis protein (bcl-2 and PARP) of FOXM1 depletion.ConclusionsOur findings indicate that highly expressed FOXM1 may help promote docetaxel resistance by inducing KIF20A expression, providing insight into novel chemotherapeutic strategies for combatting PCa docetaxel resistance.

Increased ABCC4 Expression Induced by ERRα Leads to Docetaxel Resistance via Efflux of Docetaxel in Prostate Cancer.

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.

MiR-129-5p promotes docetaxel resistance in prostate cancer by down-regulating CAMK2N1 expression.

This study focuses on the effect of miR‐129‐5p on docetaxel‐resistant (DR) prostate cancer (PCa) cells invasion, migration and apoptosis. In our study, the expression of CAMK2N1 was assessed by qRT‐PCR in PCa patient tissues and cell lines including PC‐3 and PC‐3‐DR. Cells transfected with miR‐129‐5p mimics, inhibitor, CAMK2N1 or negative controls (NC) were used to interrogate their effects on DR cell invasions, migrations and apoptosis during docetaxel (DTX) treatments. The apoptosis rate of the PCa cells was validated by flow cytometry. Relationships between miR‐129‐5p and CAMK2N1 levels were identified by qRT‐PCR and dual‐luciferase reporter assay. CAMK2N1 was found to be down‐expressed in DR PCa tissue sample, and low levels of CAMK2N1 were correlated with high docetaxel resistance and clinical prediction of poor survival. CAMK2N1 levels were decreased in DR PCa cells treated with DXT. We further explored that up‐regulation of miR‐129‐5p could promote DR PCa cells viability, invasion and migration but demote apoptosis. Involved molecular mechanism studies revealed that miR‐129‐5p reduced downstream CAMK2N1 expression to further impact on chemoresistance to docetaxel of PCa cells, indicating its vital role in PCa docetaxel resistance. Our findings revealed that miR‐129‐5p contributed to the resistance of PC‐3‐DR cells to docetaxel through suppressing CAMK2N1 expression, and thus targeting miR‐129‐5p may provide a novel therapeutic approach in sensitizing PCa to future docetaxel treatment.

Prostate Cancer-associated SPOP mutations enhance cancer cell survival and docetaxel resistance by upregulating Caprin1-dependent stress granule assembly

BackgroundThe gene encoding the E3 ubiquitin ligase substrate-binding adaptor SPOP is frequently mutated in primary prostate cancer, but how SPOP mutations contribute to prostate cancer pathogenesis remains poorly understood. Stress granules (SG) assembly is an evolutionarily conserved strategy for survival of cells under stress, and often upregulated in human cancers. We investigated the role of SPOP mutations in aberrant activation of the SG in prostate cancer and explored the relevanve of the mechanism in therapy resistance.MethodsWe identified SG nucleating protein Caprin1 as a SPOP interactor by using the yeast two hybrid methods. A series of functional analyses in cell lines, patient samples, and xenograft models were performed to investigate the biological significance and clinical relevance of SPOP regulation of SG signaling in prostate cancer.ResultsThe cytoplasmic form of wild-type (WT) SPOP recognizes and triggers ubiquitin-dependent degradation of Caprin1. Caprin1 abundance is elevated in SPOP-mutant expressing prostate cancer cell lines and patient specimens. SPOP WT suppresses SG assembly, while the prostate cancer-associated mutants enhance SG assembly in a Caprin1-dependent manner. Knockout of SPOP or expression of prostate cancer-associated SPOP mutants conferred resistance to death caused by SG inducers (e.g. docetaxel, sodium arsenite and H2O2) in prostate cancer cells.ConclusionsSG assembly is aberrantly elevated in SPOP-mutated prostate cancer. SPOP mutations cause resistance to cellular stress induced by chemtherapeutic drug such as docetaxel in prostate cancer.