scholarly journals Androgen Deprivation Induces Transcriptional Reprogramming in Prostate Cancer Cells to Develop Stem Cell-Like Characteristics

2020 ◽  
Vol 21 (24) ◽  
pp. 9568
Author(s):  
Shiv Verma ◽  
Eswar Shankar ◽  
F. Naz Cemre Kalayci ◽  
Amrita Mukunda ◽  
Malek Alassfar ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Drug Resistance ◽  
Molecular Mechanisms ◽  
Elastic Fibers ◽  
Castration Resistant Prostate Cancer ◽  
Transcriptional Reprogramming ◽  
Castration Resistant ◽  
Short Period ◽  
Novel Therapeutic Strategies ◽  
Resistant Cells

Enzalutamide, an antiandrogen, is approved for therapy of castration resistant prostate cancer. Clinical applications have shown that approximately 30% of patients acquire resistance after a short period of treatment. However, the molecular mechanisms underlying this resistance is not completely understood. To identify transcriptomic signatures associated with acquisition of drug resistance we profiled gene expression of paired enzalutamide sensitive and resistant human prostate cancer LNCaP (lymph node carcinoma of the prostate) and C4-2B cells. Overlapping genes differentially regulated in the enzalutamide resistant cells were ranked by Ingenuity Pathway Analysis and their functional validation was performed using ingenuity knowledge database followed by confirmation to correlate transcript with protein expression. Analysis revealed that genes associated with cancer stem cells, such as POU5F1 (OCT4), SOX2, NANOG, BMI1, BMP2, CD44, SOX9, and ALDH1 were markedly upregulated in enzalutamide resistant cells. Amongst the pathways enriched in the enzalutamide-resistant cells were those associated with RUNX2, hedgehog, integrin signaling, and molecules associated with elastic fibers. Further examination of a patient cohort undergoing ADT and its comparison with no-ADT group demonstrated high expression of POU5F1 (OCT4), ALDH1, and SOX2 in ADT specimens, suggesting that they may be clinically relevant therapeutic targets. Altogether, our approach exhibits the potential of integrative transcriptomic analyses to identify critical genes and pathways of antiandrogen resistance as a promising approach for designing novel therapeutic strategies to circumvent drug resistance.

Evaluation of Docetaxel-Sensitive and Docetaxel-Resistant Proteomes in PC-3 Cells

2015 ◽  
Vol 95 (1) ◽  
pp. 114-119 ◽  
Author(s):  
Shulu Zu ◽  
Weiming Ma ◽  
Pan Xiao ◽  
Yazhou Cui ◽  
Tianjia Ma ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Molecular Mechanisms ◽  
Polyacrylamide Gel Electrophoresis ◽  
Acquired Resistance ◽  
Castration Resistant Prostate Cancer ◽  
Ionization Time ◽  
Flight Mass Spectrometry ◽  
Docetaxel Resistance ◽  
Castration Resistant ◽  
Glucose Regulated Protein

Objectives: Docetaxel was the first drug with proven survival benefit in men with castration-resistant prostate cancer. Acquired resistance to docetaxel precedes fatality in castration-resistant prostate cancer. The aims of this study were to evaluate docetaxel-sensitive and docetaxel-resistant proteomes in PC-3 cells, and to investigate the molecular mechanism of docetaxel-resistant PC-3 cells. Methods: Docetaxel-resistant PC-3 cells were developed by docetaxel dose escalation. The global profiling of the protein expression was investigated in docetaxel-sensitive and docetaxel-resistant proteomes in PC-3 cells using 2-dimensional polyacrylamide gel electrophoresis/matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Results: Forty-nine differential proteins were found in docetaxel-resistant PC-3 cells in comparison with docetaxel-sensitive PC-3 cells. Expression in 29 proteins was upregulated, whereas expression in 20 proteins was downregulated. ATP synthase and galectin-1 were involved in the formation of tumor vessels; calreticulin, cathepsin D, and cofilin were involved in tumor metastasis, and GRP78 (78-kDa glucose-regulated protein) and microtubule-associated protein-6 were involved in drug resistance of tumor. Conclusion: It is suggested that a proteomic expression difference exists between docetaxel-sensitive and docetaxel-resistant PC-3 cells, which would be helpful for further understanding the molecular mechanisms of docetaxel resistance in PC-3 cells.

TACC2 Is an Androgen-Responsive Cell Cycle Regulator Promoting Androgen-Mediated and Castration-Resistant Growth of Prostate Cancer

2020 ◽  
Author(s):  
Lungwani Muungo
Keyword(s):  
Prostate Cancer ◽  
Cell Cycle ◽  
Molecular Mechanisms ◽  
Survival Rates ◽  
Tumor Formation ◽  
Castration Resistant Prostate Cancer ◽  
Cellular Models ◽  
Castration Resistant ◽  
Hormone Refractory ◽  
Immunocompromised Mice

Despite the existence of effective antiandrogen therapy for prostate cancer, the disease oftenprogresses to castration-resistant states. Elucidation of the molecular mechanisms underlying theresistance for androgen deprivation in terms of the androgen receptor (AR)-regulated pathwaysis a requisite to manage castration-resistant prostate cancer (CRPC). Using a ChIP-cloning strategy,we identified functional AR binding sites (ARBS) in the genome of prostate cancer cells. Wediscovered that a centrosome- and microtubule-interacting gene, transforming acidic coiled-coilprotein 2 (TACC2), is a novel androgen-regulated gene.Weidentified a functional AR-binding site(ARBS) including two canonical androgen response elements in the vicinity of TACC2 gene, inwhich activated hallmarks of histone modification were observed. Androgen-dependent TACC2induction is regulated by AR, as confirmed by AR knockdown or its pharmacological inhibitorbicalutamide. Using long-term androgen-deprived cells as cellular models of CRPC, we demonstratedthat TACC2 is highly expressed and contributes to hormone-refractory proliferation, assmall interfering RNA-mediated knockdown of TACC2 reduced cell growth and cell cycle progression.By contrast, in TACC2-overexpressing cells, an acceleration of the cell cycle was observed. Invivo tumor formation study of prostate cancer in castrated immunocompromised mice revealedthat TACC2 is a tumor-promoting factor. Notably, the clinical significance of TACC2 was demonstratedby a correlation between high TACC2 expression and poor survival rates. Taken togetherwith the critical roles of TACC2 in the cell cycle and the biology of prostate cancer, we infer thatthe molecule is a potential therapeutic target in CRPC

A circulating tumor cell specific RNA assay for assessment of androgen receptor signaling inhibitor sensitivity in metastatic castration-resistant prostate cancer.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 5059-5059
Author(s):  
Pai-Chi Teng ◽  
Yu Jen Jan ◽  
Junhee Yoon ◽  
Pin-Jung Chen ◽  
Jie-Fu Chen ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Drug Resistance ◽  
Androgen Receptor ◽  
Tumor Cell ◽  
Cell Lines ◽  
Circulating Tumor Cell ◽  
Z Score ◽  
Castration Resistant Prostate Cancer ◽  
Androgen Receptor Signaling ◽  
Castration Resistant

5059 Background: Our objective is to develop a circulating tumor cell (CTC)-RNA assay for characterizing clinically relevant RNA signatures for the assessment of androgen receptor signaling inhibitors (ARSIs) sensitivity in metastatic castration-resistant prostate cancer (mCRPC) patients. Methods: We developed NanoVelcro CTC-RNA Assay by combining Thermoresponsive(TR)-NanoVelcro CTC purification system with NanoString nCounter platform for CTC purification and RNA analysis. Based on the well-validated, tissue-based Prostate Cancer Classification System (PCS), we selected the most aggressive and ARSI-resistant subtype- the PCS1, for CTC analysis. We applied a rigorous bioinformatic process to develop a CTC-PCS1 panel that is specific to PC CTCs. We validated NanoVelcro CTC-RNA Assay and CTC-PCS1 panel with PC cell lines to demonstrate sensitivity and specificity of the PCS1 Z score (the likelihood estimate of the PCS1 subtype) for identifying PCS1 subtype and ARSI resistance. We then selected 31 blood samples from 23 PC patients receiving ARSIs to test in our assay. The PCS1 Z score of each sample was computed and compared with ARSI treatment sensitivity. Results: We established a 16-gene CTC-PCS1 panel that consists of CTC-specific RNA signatures. The validation studies using PC cell lines showed that the assay can detect the RNA transcripts with high sensitivity and scalability in the range of 1-100 cells. We also showed that the genes in CTC-PCS1 panel is highly expressed in PC cells. We further demonstrated that the CTC-PCS1 panel is highly specific in identifying PCS1-like samples, and the high PCS1 Z score is associated with ARSI resistance. In patient bloods, ARSI-resistant samples (ARSI-R, n=14) had significantly higher PCS1 Z scores as compared with ARSI-sensitive samples (ARSI-S, n=17) (Rank-sum test, P=0.003). In 8 patients who were initially sensitive to ARSI (ARSI-S) and later developed resistance (ARSI-R), we found that the PCS1 Z score increased from the time of ARSI-S to the time of ARSI-R (Pairwise T-test, P=0.016). Conclusions: Using our new methodology, we developed a first-in-class CTC-RNA assay and demonstrated the feasibility of transforming clinically-relevant tissue-based RNA profiling into CTC tests. This approach allows for detecting RNA expression relevant to clinical drug resistance in a non-invasive fashion, which can facilitate patient-specific treatment selection and early detection of drug resistance- a goal in precision oncology.

Optic atrophy after cabazitaxel treatment in a patient with castration-resistant prostate cancer: a case report

2018 ◽  
Vol 64 (2) ◽  
pp. 71-73 ◽  
Author(s):  
Sevda Diker ◽  
Ömer Diker
Keyword(s):  
Prostate Cancer ◽  
Drug Resistance ◽  
Case Report ◽  
Adverse Effects ◽  
Optic Neuropathy ◽  
Optic Atrophy ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Anti Cancer ◽  
New Generation

Taxanes are a group of cytotoxic anti-cancer agents used in the treatment of solid tumours. The neurotoxic adverse effects of docetaxel and paclitaxel, including optic neuropathy, are well known. Cabazitaxel is a new generation taxane showing lesser drug resistance when compared with previous ones. Optic atrophy due to the use of cabazitaxel has not been previously reported. Herein, we report a patient with prostate cancer who developed optic atrophy after cabazitaxel treatment.

scholarly journals PMA induces androgen receptor downregulation and cellular apoptosis in prostate cancer cells

2014 ◽  
Vol 53 (1) ◽  
pp. 31-41 ◽  
Author(s):  
Momoe Itsumi ◽  
Masaki Shiota ◽  
Akira Yokomizo ◽  
Ario Takeuchi ◽  
Eiji Kashiwagi ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Cancer Cells ◽  
Therapeutic Effects ◽  
Castration Resistant Prostate Cancer ◽  
Lncap Cells ◽  
Prostate Cancer Cells ◽  
Castration Resistant ◽  
Cellular Apoptosis ◽  
Resistant Cells

Phorbol 12-myristate 13-acetate (PMA) induces cellular apoptosis in prostate cancer cells, the growth of which is governed by androgen/androgen receptor (AR) signaling, but the mechanism by which PMA exerts this effect remains unknown. Therefore, in this study, we investigated the mechanistic action of PMA in prostate cancer cells with regard to AR. We showed that PMA decreased E2F1 as well as AR expression in androgen-dependent prostate cancer LNCaP cells. Furthermore, PMA activated JNK and p53 signaling, resulting in the induction of cellular apoptosis. In LNCaP cells, androgen deprivation and a novel anti-androgen enzalutamide (MDV3100) augmented cellular apoptosis induced by PMA. Moreover, castration-resistant prostate cancer (CRPC) C4-2 cells were more sensitive to PMA compared with LNCaP cells and were sensitized to PMA by enzalutamide. Finally, the expression of PKC, E2F1, and AR was diminished in PMA-resistant cells, indicating that the gain of independence from PKC, E2F1, and AR functions leads to PMA resistance. In conclusion, PMA exerted its anti-cancer effects via the activation of pro-apoptotic JNK/p53 and inhibition of pro-proliferative E2F1/AR in prostate cancer cells including CRPC cells. The therapeutic effects of PMA were augmented by androgen deletion and enzalutamide in androgen-dependent prostate cancer cells, as well as by enzalutamide in castration-resistant cells. Taken together, PMA derivatives may be promising therapeutic agents for treating prostate cancer patients including CRPC patients.

scholarly journals Identification of Key Genes and Molecular Mechanisms Associated With Docetaxel Resistance in Castration Resistant Prostate Cancer Based on Bioinformatics Analysis

2020 ◽  
Author(s):  
Yu Liu ◽  
Changpeng Hu ◽  
Qian Zhang ◽  
Wuyi Liu ◽  
Guobing Li ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Molecular Mechanisms ◽  
Epithelial Mesenchymal Transition ◽  
Castration Resistant Prostate Cancer ◽  
Mesenchymal Transition ◽  
Docetaxel Resistance ◽  
Castration Resistant ◽  
E2f Transcription Factor ◽  
Key Genes

Abstract BackgroundCastration resistant prostate cancer (CRPC) is one of the most common solid tumor with high mortality and limited therapeutic options, and docetaxel is the first-line chemotherapy for patients. However, the long-term use of docetaxel has limited its clinical applications. The aim of this study was to identify docetaxel-resistant key genes and molecular mechanisms. ResultsTUBB4A (Class IVa beta-tubulin), SRPX (Sushi repeat containing protein, X chromosome) and CSRP2 (Cysteine and glycine rich protein 2) were finally identified as the key genes tightly related to docetaxel resistance. TUBB4A and CSRP2 may participate in docetaxel resistance by E2F transcription factor and MYC proto-Oncogene in the process of cell cycle, and SRPX may participate in docetaxel resistance by epithelial–mesenchymal transition (EMT) and P53 pathway. ConclusionTUBB4A, SRPX and CSRP2 may be the key genes associated with docetaxel resistance, which could be prognostic biomarkers for docetaxel resistance in CRPC.

Sign in / Sign up

Export Citation Format

Share Document