Abstract Purpose: Enzalutamide, a second-generation antiandrogen, was recently approved for the treatment of castration-resistant prostate cancer (CRPC) in patients who no longer respond to docetaxel. Despite these advances that provide temporary respite, resistance enzalutamide occurs frequently. Androgen receptor (AR) splice variants such as AR-V7 have been shown drive growth and enzalutamide. This study designed identify inhibitors AR test its ability overcome Experimental Design: The...

The introduction of enzalutamide and abiraterone has led to improvement in the treatment metastatic castration-resistant prostate cancer. However, acquired resistance therapies frequently develops within a short period many patients. In present study, we developed enzalutamide-resistant cancer cells an effort understand mechanisms resistance. Global gene-expression analysis showed that steroid biosynthesis pathway is activated cells. One crucial steroidogenic enzymes, AKR1C3, was...

Abstract Resistance of prostate cancer cells to the next-generation antiandrogen enzalutamide may be mediated by a multitude survival signaling pathways. In this study, we tested whether increased expression NF-κB2/p52 induces cell resistance and response is aberrant androgen receptor (AR) activation AR splice variant production. LNCaP stably expressing exhibited higher rates than controls when treated with enzalutamide. C4-2B CWR22Rv1 chronically were found express levels NF-κB2/p52....

Castration-resistant prostate cancer (CRPC) remains dependent on androgen receptor (AR) signaling. Alternative splicing of the AR to generate constitutively active, ligand-independent variants is one principal mechanisms that promote development resistance next-generation antiandrogens such as enzalutamide. Here, we demonstrate factor heterogeneous nuclear RNA-binding protein A1 (hnRNPA1) plays a pivotal role in generation splice AR-V7. hnRNPA1 overexpressed tumors compared with benign...

Abstract BACKGROUND Docetaxel is the first line treatment for castration resistant prostate cancer (CRPC). However, docetaxel resistance rapidly develops. Identifying critical mechanisms giving rise to major challenge in advanced cancer. METHODS The effects of on human DU145, PC3, LNCaP, and C4‐2 cells were examined cell culture, p53 expression analyzed by Western blot analysis. potential role sensitivity was tested either silencing using shRNA or overexpression introducing wild‐type p53....

Abstract Docetaxel is the first-line standard treatment for castration-resistant prostate cancer. However, relapse eventually occurs due to development of resistance docetaxel. To unravel mechanism acquired docetaxel resistance, we established docetaxel-resistant cancer cells, TaxR, from C4-2B cells. The IC50 in TaxR cells was about 70-fold higher than parental Global gene expression analysis revealed alteration a total 1,604 genes, with 52% being upregulated and 48% downregulated. ABCB1,...

Abstract Abiraterone suppresses intracrine androgen synthesis via inhibition of CYP17A1. However, clinical evidence suggests that is not fully inhibited by abiraterone and the sustained production may lead to disease relapse. In present study, we identified AKR1C3, an important enzyme in steroidogenesis pathway, as a critical mechanism driving resistance through increasing enhancing signaling. We found overexpression AKR1C3 confers while downregulation resensitizes resistant cells treatment....

PURPOSE It is known that over expression of IL6 in prostate cancer cells confer enzalutamide resistance and this may occur through constitutive Stat3 activation. Additionally, recent pre-clinical studies suggested might have the potential adverse effect inducing metastasis via This study aimed to target activation improve therapy. EXPERIMENTAL DESIGN Sensitivity was tested using cell growth assays clonogenic assays. Wound healing invasion were performed determine migration vitro....

Protein homeostasis (proteostasis) is a potential mechanism that contributes to cancer cell survival and drug resistance. Constitutively active androgen receptor (AR) variants confer anti-androgen resistance in advanced prostate cancer. However, the role of proteostasis involved next generation mechanisms AR variant regulation are poorly defined. Here we show ubiquitin-proteasome-system (UPS) suppressed enzalutamide/abiraterone resistant AR/AR-V7 requires interaction E3 ubiquitin ligase...

// Chengfei Liu 1 , Cameron Armstrong Yezi Zhu 1, 2 Wei Lou Allen C. Gao 2, 3 Department of Urology, University California Davis, CA, USA Graduate Program in Pharmacology and Toxicology, UC Davis Comprehensive Cancer Center, Correspondence to: Gao, e-mail: acgao@ucdavis.edu Keywords: prostate cancer, niclosamide, abiraterone, androgen receptor variant, resistance Received: December 10, 2015 Accepted: March 2016 Published: 30, ABSTRACT Considerable evidence from both clinical experimental...

Abstract Niclosamide has preclinical activity against a wide range of cancers. In prostate cancer, it inhibits androgen receptor variant 7 and synergizes with abiraterone. The approved niclosamide formulation poor oral bioavailability. primary objective this phase Ib trial was to identify maximum tolerated dose (MTD) recommended 2 (RP2D) novel reformulated orally-bioavailable niclosamide/PDMX1001 in combination abiraterone prednisone men castration-resistant cancer (CRPC). Eligible patients...

Objective To develop and validate a risk prediction model related to inflammatory nutritional indexes for postoperative pulmonary infection (POI) after radical colorectal cancer (CRC) surgery. Design Cross-sectional study. Participants This study analysed 866 CRC patients surgery at tertiary hospital in China. Methods Univariable multivariable logistic regression (LR) analyses were used explore influence factors of POI. Predictive models constructed using LR, random forest, support vector...

Abstract PURPOSE Use of enzalutamide has improved the treatment advanced prostate cancer. However, resistance to can develop frequently in initial responders. This study aimed test whether overexpression IL‐6 and constitutive activation Stat3 cancer cells increase enzalutamide. EXPERIMENTAL DESIGN Sensitivity was tested using cell growth assays clonogenic assays. Quantitative reverse transcription‐PCR, ELISA, Western blotting were performed detect expression levels IL‐6, c‐Myc, survivin, AR....

BACKGROUND Paracrine interleukin‐6 (IL‐6) can mediate neuroendocrine (NE) features, including the acquisition of a neurite‐like phenotype and growth arrest in prostate cancer cells. However, little is known about mechanisms underlying differentiation induced by IL‐6. METHODS Immunoblotting was performed to determine status RE1‐silencing transcription factor (REST) markers such as Neuron‐specific Enolase (NSE), chromogranin A synaptophysin LNCaP cells treated with To further study impact...

Abstract The mechanisms resulting in resistance to next-generation antiandrogens castration-resistant prostate cancer are incompletely understood. Numerous studies have determined that constitutively active androgen receptor (AR) signaling or full-length AR bypass may contribute the resistance. Previous established AKR1C3 and AR-V7 play important roles enzalutamide abiraterone In present study, we found increases expression resistant cells through enhancing protein stability via activation...

Abstract The next-generation antiandrogen drugs, XTANDI (enzalutamide), ZYTIGA (abiraterone acetate), ERLEADA (apalutamide) and NUBEQA (darolutamide) extend survival times improve quality of life in patients with advanced prostate cancer. Despite these advances, resistance occurs frequently there is currently no definitive cure for castration-resistant Our previous studies identified that similar mechanisms to enzalutamide or abiraterone occur following treatment cross-resistance exists...

Background Emerging data suggest that patients with enzalutamide-treated prostate cancer increased programmed death-ligand 1 (PD-L1) expression may benefit from anti-PD-L1 treatment. Unfortunately, the Phase III IMbassador250 clinical trial revealed combination of atezolizumab (a PD-L1 inhibitor) and enzalutamide failed to extend overall survival in castration-resistant (CRPC). However, mechanisms underlying treatment failure remain unknown. Methods Human CRPC C4-2B cells murine Myc-CaP were...

Olaparib is a pioneering PARP inhibitor (PARPi) approved for treating castration-resistant prostate cancer (CRPC) tumors harboring DNA repair defects, but clinical resistance has been documented. To study acquired resistance, we developed Olaparib-resistant (OlapR) cell lines through chronic treatment of LNCaP and C4-2B lines. Here, found that IGFBP3 highly expressed in intrinsic (Rv1) models resistance. We show expression promotes by enhancing capacity activation EGFR DNA-PKcs. depletion...

Abstract BACKGROUND Signal transducer and activator of transcription 3 (Stat3) is an oncogenic transcriptional factor that plays a critical role in carcinogenesis cancer progression potential therapeutic target. Sanguinarine, benzophenanthridine alkaloid derived primarily from the bloodroot plant, was identified previously as novel inhibitor survivin selectively kills prostate cells over “normal” epithelial cells. METHODS DU145, C4‐2B, LNCaP were treated with sanguinarine. The...

Previous studies show that inhibition of ABCB1 expression overcomes acquired docetaxel resistance in C4-2B-TaxR cells. In this study, we examined whether antiandrogens, such as bicalutamide and enzalutamide, could inhibit activity overcome to docetaxel.ABCB1 efflux was determined using a rhodamine assay. ATPase by Pgp-Glo assay systems. The effects the antiandrogens enzalutamide on sensitivity were cell growth assays tumor vivo.We found ATP-binding cassette transporter through blocking...

Advancements in research have added several new therapies for castration-resistant prostate cancer (CRPC), greatly augmenting our ability to treat patients. However, CRPC remains an incurable disease due the development of therapeutic resistance and existence cross-resistance between available therapies. Understanding interplay different treatments will lead improved sequencing creation combinations that overcome prolong survival. Whether there exists docetaxel next-generation taxane...

Abstract Activation of the androgen receptor (AR) and its splice variants is linked to advanced prostate cancer drives resistance antiandrogens. The roles AR in development deprivation therapy (ADT) bicalutamide treatment, however, are still incompletely understood. To determine whether play a role resistance, we developed bicalutamide-resistant LNCaP cells (LNCaP-BicR) found that these resistant express significantly increased levels variants, particularly AR-V7, both at mRNA protein...

Complement factor 5a (C5a) interaction with its receptor (C5aR1) contributes to the pathogenesis of inflammatory diseases, including acute kidney injury. However, role in chronic inflammation, particularly pathogen-associated disorders, is largely unknown. Here we tested whether development inflammation and renal fibrosis dependent on C5aR1 a murine model pyelonephritis. C5aR1-deficient (C5aR1-/-) mice showed significant reduction bacterial load, tubule injury tubulointerstitial kidneys...