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Activation of GRP/GRP-R signaling contributes to castration-resistant prostate cancer progression.
Qiao J, Grabowska MM, Forestier-Roman IS, Mirosevich J, Case TC, Chung DH, Cates JM, Matusik RJ, Manning HC, Jin R
(2016) Oncotarget 7: 61955-61969
MeSH Terms: Adenocarcinoma, Androgen Antagonists, Androgens, Antineoplastic Agents, Cell Line, Tumor, Disease Progression, Gastrin-Releasing Peptide, Gene Expression Regulation, Neoplastic, Genetic Variation, Humans, Male, Prostatic Neoplasms, Castration-Resistant, RNA Splicing, Receptors, Androgen, Receptors, Bombesin, Signal Transduction, Transcription, Genetic
Show Abstract · Added April 6, 2017
Numerous studies indicate that androgen receptor splice variants (ARVs) play a critical role in the development of castration-resistant prostate cancer (CRPC), including the resistance to the new generation of inhibitors of androgen receptor (AR) action. Previously, we demonstrated that activation of NF-κB signaling increases ARVs expression in prostate cancer (PC) cells, thereby promoting progression to CRPC. However, it is unclear how NF-κB signaling is activated in CRPC. In this study, we report that long-term treatment with anti-androgens increases a neuroendocrine (NE) hormone - gastrin-releasing peptide (GRP) and its receptor (GRP-R) expression in PC cells. In addition, activation of GRP/GRP-R signaling increases ARVs expression through activating NF-κB signaling. This results in an androgen-dependent tumor progressing to a castrate resistant tumor. The knock-down of AR-V7 restores sensitivity to antiandrogens of PC cells over-expressing the GRP/GRP-R signaling pathway. These findings strongly indicate that the axis of Androgen-Deprivation Therapy (ADT) induces GRP/GRP-R activity, activation NF-κB and increased levels of AR-V7 expression resulting in progression to CRPC. Both prostate adenocarcinoma and small cell NE prostate cancer express GRP-R. Since the GRP-R is clinically targetable by analogue-based approach, this provides a novel therapeutic approach to treat advanced CRPC.
0 Communities
3 Members
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17 MeSH Terms
NF-κB and androgen receptor variant 7 induce expression of SRD5A isoforms and confer 5ARI resistance.
Austin DC, Strand DW, Love HL, Franco OE, Grabowska MM, Miller NL, Hameed O, Clark PE, Matusik RJ, Jin RJ, Hayward SW
(2016) Prostate 76: 1004-18
MeSH Terms: 3-Oxo-5-alpha-Steroid 4-Dehydrogenase, 5-alpha Reductase Inhibitors, Animals, Apoptosis, Drug Resistance, Gene Expression, Gene Knockdown Techniques, Humans, Isoenzymes, Lower Urinary Tract Symptoms, Male, Membrane Proteins, Mice, Mice, Nude, NF-kappa B, Orchiectomy, Prostate, Prostatic Hyperplasia, Prostatic Neoplasms, Castration-Resistant, Receptors, Androgen, Testosterone, Treatment Failure, Up-Regulation
Show Abstract · Added April 18, 2017
BACKGROUND - Benign prostatic hyperplasia (BPH) is treated with 5α-reductase inhibitors (5ARI). These drugs inhibit the conversion of testosterone to dihydrotestosterone resulting in apoptosis and prostate shrinkage. Most patients initially respond to 5ARIs; however, failure is common especially in inflamed prostates, and often results in surgery. This communication examines a link between activation of NF-κB and increased expression of SRD5A2 as a potential mechanism by which patients fail 5ARI therapy.
METHODS - Tissue was collected from "Surgical" patients, treated specifically for lower urinary tract symptoms secondary to advanced BPH; and, cancer free transition zone from "Incidental" patients treated for low grade, localized peripheral zone prostate cancer. Clinical, molecular and histopathological profiles were analyzed. Human prostatic stromal and epithelial cell lines were genetically modified to regulate NF-κB activity, androgen receptor (AR) full length (AR-FL), and AR variant 7 (AR-V7) expression.
RESULTS - SRD5A2 is upregulated in advanced BPH. SRD5A2 was significantly associated with prostate volume determined by Transrectal Ultrasound (TRUS), and with more severe lower urinary tract symptoms (LUTS) determined by American Urological Association Symptom Score (AUASS). Synthesis of androgens was seen in cells in which NF-κB was activated. AR-FL and AR-V7 expression increased SRD5A2 expression while forced activation of NF-κB increased all three SRD5A isoforms. Knockdown of SRD5A2 in the epithelial cells resulted in significant reduction in proliferation, AR target gene expression, and response to testosterone (T). In tissue recombinants, canonical NF-κB activation in prostatic epithelium elevated all three SRD5A isoforms and resulted in in vivo growth under castrated conditions.
CONCLUSION - Increased BPH severity in patients correlates with SRD5A2 expression. We demonstrate that NF-κB and AR-V7 upregulate SRD5A expression providing a mechanism to explain failure of 5ARI therapy in BPH patients. Prostate 76:1004-1018, 2016. © 2016 Wiley Periodicals, Inc.
© 2016 Wiley Periodicals, Inc.
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23 MeSH Terms
Enzalutamide Versus Bicalutamide in Castration-Resistant Prostate Cancer: The STRIVE Trial.
Penson DF, Armstrong AJ, Concepcion R, Agarwal N, Olsson C, Karsh L, Dunshee C, Wang F, Wu K, Krivoshik A, Phung D, Higano CS
(2016) J Clin Oncol 34: 2098-106
MeSH Terms: Adult, Aged, Androgen Antagonists, Anilides, Antineoplastic Agents, Double-Blind Method, Humans, Male, Middle Aged, Nitriles, Phenylthiohydantoin, Prostate-Specific Antigen, Prostatic Neoplasms, Castration-Resistant, Tosyl Compounds
Show Abstract · Added February 4, 2016
PURPOSE - Enzalutamide, a potent oral androgen receptor inhibitor, improves survival in men with metastatic castration-resistant prostate cancer (CRPC) before and after chemotherapy. Bicalutamide, a nonsteroidal antiandrogen, is widely used to treat men with nonmetastatic or metastatic CRPC. The efficacy and safety of these drugs were compared in this randomized, double-blind, phase II study of men with CRPC.
PATIENTS AND METHODS - A total of 396 men with nonmetastatic (n = 139) or metastatic (n = 257) CRPC were randomly assigned to enzalutamide 160 mg per day (n = 198) or bicalutamide 50 mg per day (n = 198). Androgen deprivation therapy was continued in both arms. The primary end point was progression-free survival (PFS).
RESULTS - Enzalutamide reduced the risk of progression or death by 76% compared with bicalutamide (hazard ratio [HR], 0.24; 95% CI, 0.18 to 0.32; P < .001). Median PFS was 19.4 months with enzalutamide versus 5.7 months with bicalutamide. Enzalutamide resulted in significant improvements in all key secondary end points: time to prostate-specific antigen progression (HR, 0.19; 95% CI, 0.14 to 0.26; P < .001); proportion of patients with a ≥ 50% prostate-specific antigen response (81% v 31%; P < .001); and radiographic PFS in metastatic patients (HR, 0.32; 95% CI, 0.21 to 0.50; P < .001). Beneficial effects with enzalutamide were observed in both nonmetastatic and metastatic subgroups. The observed adverse event profile was consistent with that from phase III enzalutamide trials.
CONCLUSION - Enzalutamide significantly reduced risk of prostate cancer progression or death compared with bicalutamide in patients with nonmetastatic or metastatic CRPC.
© 2016 by American Society of Clinical Oncology.
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14 MeSH Terms
Competition between the Brain and Testes under Selenium-Compromised Conditions: Insight into Sex Differences in Selenium Metabolism and Risk of Neurodevelopmental Disease.
Pitts MW, Kremer PM, Hashimoto AC, Torres DJ, Byrns CN, Williams CS, Berry MJ
(2015) J Neurosci 35: 15326-38
MeSH Terms: Age Factors, Animals, Brain, Castration, Dizocilpine Maleate, Epilepsy, Reflex, Exploratory Behavior, Female, Gene Expression Regulation, Glutamate Decarboxylase, Lyases, Male, Maze Learning, Mice, Mice, Inbred C57BL, Mice, Transgenic, Motor Activity, Nerve Tissue Proteins, Neurodevelopmental Disorders, Selenium, Selenoprotein P, Sex Factors, Transcription Factors
Show Abstract · Added March 29, 2016
UNLABELLED - Selenium (Se) is essential for both brain development and male fertility. Male mice lacking two key genes involved in Se metabolism (Scly(-/-)Sepp1(-/-) mice), selenoprotein P (Sepp1) and Sec lyase (Scly), develop severe neurological dysfunction, neurodegeneration, and audiogenic seizures that manifest beginning in early adulthood. We demonstrate that prepubescent castration of Scly(-/-)Sepp1(-/-) mice prevents behavioral deficits, attenuates neurodegeneration, rescues maturation of GABAergic inhibition, and increases brain selenoprotein levels. Moreover, castration also yields similar neuroprotective benefits to Sepp1(-/-) and wild-type mice challenged with Se-deficient diets. Our data show that, under Se-compromised conditions, the brain and testes compete for Se utilization, with concomitant effects on neurodevelopment and neurodegeneration.
SIGNIFICANCE STATEMENT - Selenium is an essential trace element that promotes male fertility and brain function. Herein, we report that prepubescent castration provides neuroprotection by increasing selenium-dependent antioxidant activity in the brain, revealing a competition between the brain and testes for selenium utilization. These findings provide novel insight into the interaction of sex and oxidative stress upon the developing brain and have potentially significant implications for the prevention of neurodevelopmental disorders characterized by aberrant excitatory/inhibitory balance, such as schizophrenia and epilepsy.
Copyright © 2015 the authors 0270-6474/15/3515326-13$15.00/0.
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23 MeSH Terms
PIM kinase inhibitor AZD1208 for treatment of MYC-driven prostate cancer.
Kirschner AN, Wang J, van der Meer R, Anderson PD, Franco-Coronel OE, Kushner MH, Everett JH, Hameed O, Keeton EK, Ahdesmaki M, Grosskurth SE, Huszar D, Abdulkadir SA
(2015) J Natl Cancer Inst 107:
MeSH Terms: Administration, Oral, Allografts, Animals, Antineoplastic Agents, Apoptosis, Biphenyl Compounds, Cell Hypoxia, Cell Proliferation, Down-Regulation, Gene Expression Regulation, Enzymologic, Gene Expression Regulation, Neoplastic, Genes, myc, Humans, Male, Mice, Prostatic Neoplasms, Prostatic Neoplasms, Castration-Resistant, Protein Kinase Inhibitors, Proto-Oncogene Proteins c-pim-1, Thiazolidines, Tumor Suppressor Protein p53, Xenograft Model Antitumor Assays
Show Abstract · Added January 21, 2015
BACKGROUND - PIM1 kinase is coexpressed with c-MYC in human prostate cancers (PCs) and dramatically enhances c-MYC-induced tumorigenicity. Here we examine the effects of a novel oral PIM inhibitor, AZD1208, on prostate tumorigenesis and recurrence.
METHODS - A mouse c-MYC/Pim1-transduced tissue recombination PC model, Myc-CaP allografts, and human PC xenografts were treated with AZD1208 (n = 5-11 per group). Androgen-sensitive and castrate-resistant prostate cancer (CRPC) models were studied as well as the effects of hypoxia and radiation. RNA sequencing was used to analyze drug-induced gene expression changes. Results were analyzed with χ(2) test. Student's t test and nonparametric Mann-Whitney rank sum U Test. All statistical tests were two-sided.
RESULTS - AZD1208 inhibited tumorigenesis in tissue recombinants, Myc-CaP, and human PC xenograft models. PIM inhibition decreased c-MYC/Pim1 graft growth by 54.3 ± 39% (P < .001), decreased cellular proliferation by 46 ± 14% (P = .016), and increased apoptosis by 326 ± 170% (P = .039). AZD1208 suppressed multiple protumorigenic pathways, including the MYC gene program. However, it also downregulated the p53 pathway. Hypoxia and radiation induced PIM1 in prostate cancer cells, and AZD1208 functioned as a radiation sensitizer. Recurrent tumors postcastration responded transiently to either AZD1208 or radiation treatment, and combination treatment resulted in more sustained inhibition of tumor growth. Cell lines established from recurrent, AZD1208-resistant tumors again revealed downregulation of the p53 pathway. Irradiated AZD1208-treated tumors robustly upregulated p53, providing a possible mechanistic explanation for the effectiveness of combination therapy. Finally, an AZD1208-resistant gene signature was found to be associated with biochemical recurrence in PC patients.
CONCLUSIONS - PIM inhibition is a potential treatment for MYC-driven prostate cancers including CRPC, and its effectiveness may be enhanced by activators of the p53 pathway, such as radiation.
© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.
0 Communities
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22 MeSH Terms
Inhibition of NF-kappa B signaling restores responsiveness of castrate-resistant prostate cancer cells to anti-androgen treatment by decreasing androgen receptor-variant expression.
Jin R, Yamashita H, Yu X, Wang J, Franco OE, Wang Y, Hayward SW, Matusik RJ
(2015) Oncogene 34: 3700-10
MeSH Terms: Androgen Antagonists, Anilides, Antineoplastic Agents, Antineoplastic Combined Chemotherapy Protocols, Boronic Acids, Bortezomib, Cell Line, Tumor, Humans, Male, NF-kappa B, Nitriles, Prostatic Neoplasms, Castration-Resistant, Pyrazines, Receptors, Androgen, Signal Transduction, Tosyl Compounds, Xenograft Model Antitumor Assays
Show Abstract · Added January 20, 2015
Androgen receptor splicing variants (ARVs) that lack the ligand-binding domain (LBD) are associated with the development of castration-resistant prostate cancer (CRPC), including resistance to the new generation of high-affinity anti-androgens. However, the mechanism by which ARV expression is regulated is not fully understood. In this study, we show that the activation of classical nuclear factor-kappa B (NF-κB) signaling increases the expression of ARVs in prostate cancer (PCa) cells and converts androgen-sensitive PCa cells to become androgen-insensitive, whereas downregulation of NF-κB signaling inhibits ARV expression and restores responsiveness of CRPC to anti-androgen therapy. In addition, we demonstrated that combination of anti-androgen with NF-κB-targeted therapy inhibits efficiently tumor growth of human CRPC xenografts. These results indicate that induction of ARVs by activated NF-κB signaling in PCa cells is a critical mechanism by which the PCa progresses to CRPC. This has important implications as it can prolong the survival of CRPC patients by restoring the tumors to once again respond to conventional androgen-deprivation therapy (ADT).
1 Communities
3 Members
0 Resources
17 MeSH Terms
Activation of Wnt/β-catenin signaling in a subpopulation of murine prostate luminal epithelial cells induces high grade prostate intraepithelial neoplasia.
Valkenburg KC, Yu X, De Marzo AM, Spiering TJ, Matusik RJ, Williams BO
(2014) Prostate 74: 1506-20
MeSH Terms: Adenomatous Polyposis Coli Protein, Animals, Castration, Enzyme-Linked Immunosorbent Assay, Epithelial Cells, Immunohistochemistry, Male, Mice, Prostate, Prostatic Intraepithelial Neoplasia, Prostatic Neoplasms, Reverse Transcriptase Polymerase Chain Reaction, Tamoxifen, Wnt Proteins, Wnt Signaling Pathway, beta Catenin
Show Abstract · Added January 20, 2015
BACKGROUND - Wnt/β-catenin signaling is important for prostate development and cancer in humans. Activation of this pathway in differentiated luminal cells of mice induces high-grade prostate intraepithelial neoplasia (HGPIN). Though the cell of origin of prostate cancer has yet to be conclusively identified, a castration-resistant Nkx3.1-expressing cell (CARN) may act as a cell of origin for prostate cancer.
METHODS - To activate Wnt/β-catenin signaling in CARNs, we crossed mice carrying tamoxifen-inducible Nkx3.1-driven Cre to mice containing loxP sites in order to either conditionally knock out adenomatous polyposis coli (Apc) or constitutively activate β-catenin directly. We then castrated and hormonally regenerated these mice to target the CARN population.
RESULTS - Loss of Apc in hormonally normal mice induced HGPIN; however, after one or more rounds of castration and hormonal regeneration, Apc-null CARNs disappeared. Alternatively, when β-catenin was constitutively activated under the same conditions, HGPIN was apparent.
CONCLUSION - Activation of Wnt/β-catenin signaling via Apc deletion is sufficient to produce HGPIN in hormonally normal mice. Loss of Apc may destabilize the CARN population under regeneration conditions. When β-catenin is constitutively activated, HGPIN occurs in hormonally regenerated mice. A second genetic hit is likely required to cause progression to carcinoma and metastasis.
© 2014 Wiley Periodicals, Inc.
1 Communities
1 Members
0 Resources
16 MeSH Terms
NF-κB gene signature predicts prostate cancer progression.
Jin R, Yi Y, Yull FE, Blackwell TS, Clark PE, Koyama T, Smith JA, Matusik RJ
(2014) Cancer Res 74: 2763-72
MeSH Terms: Animals, Carcinogenesis, Cell Line, Tumor, Disease Models, Animal, Disease Progression, Gene Expression Profiling, Gene Regulatory Networks, Humans, I-kappa B Proteins, Male, Mice, Mice, Transgenic, NF-KappaB Inhibitor alpha, NF-kappa B, Neoplasm Metastasis, Prostatic Neoplasms, Prostatic Neoplasms, Castration-Resistant, Signal Transduction
Show Abstract · Added May 27, 2014
In many patients with prostate cancer, the cancer will be recurrent and eventually progress to lethal metastatic disease after primary treatment, such as surgery or radiation therapy. Therefore, it would be beneficial to better predict which patients with early-stage prostate cancer would progress or recur after primary definitive treatment. In addition, many studies indicate that activation of NF-κB signaling correlates with prostate cancer progression; however, the precise underlying mechanism is not fully understood. Our studies show that activation of NF-κB signaling via deletion of one allele of its inhibitor, IκBα, did not induce prostatic tumorigenesis in our mouse model. However, activation of NF-κB signaling did increase the rate of tumor progression in the Hi-Myc mouse prostate cancer model when compared with Hi-Myc alone. Using the nonmalignant NF-κB-activated androgen-depleted mouse prostate, a NF-κB-activated recurrence predictor 21 (NARP21) gene signature was generated. The NARP21 signature successfully predicted disease-specific survival and distant metastases-free survival in patients with prostate cancer. This transgenic mouse model-derived gene signature provides a useful and unique molecular profile for human prostate cancer prognosis, which could be used on a prostatic biopsy to predict indolent versus aggressive behavior of the cancer after surgery.
©2014 American Association for Cancer Research.
3 Communities
5 Members
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18 MeSH Terms
Nrf1 and Nrf2 transcription factors regulate androgen receptor transactivation in prostate cancer cells.
Schultz MA, Hagan SS, Datta A, Zhang Y, Freeman ML, Sikka SC, Abdel-Mageed AB, Mondal D
(2014) PLoS One 9: e87204
MeSH Terms: Analysis of Variance, Cell Line, Tumor, Chromatin Immunoprecipitation, DNA Primers, Dihydrotestosterone, Electrophoretic Mobility Shift Assay, Humans, Immunoblotting, Luciferases, Male, NF-E2-Related Factor 2, Nuclear Respiratory Factor 1, Prostatic Neoplasms, Castration-Resistant, Real-Time Polymerase Chain Reaction, Receptors, Androgen, Transcriptional Activation
Show Abstract · Added March 13, 2014
Despite androgen deprivation therapy (ADT), persistent androgen receptor (AR) signaling enables outgrowth of castration resistant prostate cancer (CRPC). In prostate cancer (PCa) cells, ADT may enhance AR activity through induction of oxidative stress. Herein, we investigated the roles of Nrf1 and Nrf2, transcription factors that regulate antioxidant gene expression, on hormone-mediated AR transactivation using a syngeneic in vitro model of androgen dependent (LNCaP) and castration resistant (C4-2B) PCa cells. Dihydrotestosterone (DHT) stimulated transactivation of the androgen response element (ARE) was significantly greater in C4-2B cells than in LNCaP cells. DHT-induced AR transactivation was coupled with higher nuclear translocation of p65-Nrf1 in C4-2B cells, as compared to LNCaP cells. Conversely, DHT stimulation suppressed total Nrf2 levels in C4-2B cells but elevated total Nrf2 levels in LNCaP cells. Interestingly, siRNA mediated silencing of Nrf1 attenuated AR transactivation while p65-Nrf1 overexpression enhanced AR transactivation. Subsequent studies showed that Nrf1 physically interacts with AR and enhances AR's DNA-binding activity, suggesting that the p65-Nrf1 isoform is a potential AR coactivator. In contrast, Nrf2 suppressed AR-mediated transactivation by stimulating the nuclear accumulation of the p120-Nrf1 which suppressed AR transactivation. Quantitative RT-PCR studies further validated the inductive effects of p65-Nrf1 isoform on the androgen regulated genes, PSA and TMPRSS2. Therefore, our findings implicate differential roles of Nrf1 and Nrf2 in regulating AR transactivation in PCa cells. Our findings also indicate that the DHT-stimulated increase in p65-Nrf1 and the simultaneous suppression of both Nrf2 and p120-Nrf1 ultimately facilitates AR transactivation in CRPC cells.
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16 MeSH Terms
A urologic oncology roundtable discussion: the role of disease monitoring in treatment decision-making for patients with metastatic castration-resistant prostate cancer.
Shore ND, Concepcion R, Barocas DA
(2013) Hosp Pract (1995) 41: 78-80
MeSH Terms: Androstenols, Antineoplastic Agents, Cancer Vaccines, Decision Making, Drug Monitoring, Humans, Immunotherapy, Male, Medical Oncology, Middle Aged, Neoplasm Metastasis, Practice Guidelines as Topic, Prostatic Neoplasms, Castration-Resistant
Show Abstract · Added March 7, 2014
A recent Elsevier survey of 200 urologists and oncologists who treat patients with castration-resistant prostate cancer (CRPC) identified a lack of physician confidence in understanding and using current clinical practices regarding the identification, treatment, and management of patients with CRPC. In response to this knowledge gap, a urologic oncology physician roundtable discussion was convened and a companion summary article created to provide a knowledge-based perspective for optimizing the identification, monitoring, and treatment of patients with metastatic CRPC (http://prostatecancer.urologiconcology.org/). Leading urology experts were selected to discuss how CRPC is defined and monitored, and to elaborate (through the presentation of 2 different cases) on considerations of how the currently approved chemotherapeutics, immunotherapy, and oral androgen inhibition agents can be used in the treatment of metastatic CRPC.
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13 MeSH Terms