Aberrant tumor metabolism to enable glucocorticoid receptor takeover in enzalutamide-resistant prostate cancer.

2017 ◽  
Vol 35 (6_suppl) ◽  
pp. 157-157
Author(s):  
Nima Sharifi ◽  
Jianneng Li ◽  
Mohammad Alyamani ◽  
Ao Zhang ◽  
Kai-Hsiung Chang ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Glucocorticoid Receptor ◽  
High Performance ◽  
Therapeutic Effects ◽  
Ubiquitin E3 Ligase ◽  
Xenograft Models ◽  
Metabolic Mechanism ◽  
Cancer Tissues ◽  
Expression Loss ◽  
Stimulation Of

157 Background: Prostate cancer is driven by androgen stimulation of the androgen receptor (AR). The next-generation AR antagonist, enzalutamide, prolongs progression-free and overall survival, but resistance and lethal disease eventually prevail. Emerging data suggest that the glucocorticoid receptor (GR) is upregulated in this context, stimulating expression of approximately 50% of genes normally stimulated by AR, thereby permitting continued growth despite AR blockade. However, countering this mechanism by administration of GR antagonists is problematic because GR is essential for life. Methods: We assessed the effects of enzalutamide on metabolism of cortisol to cortisone in the LAPC4 and VCaP models of prostate cancer using [3H]-cortisol and high performance liquid chromatography. Expression of 11β-hydroxysteroid dehydrogenase-2, encoding the enzyme 11βHSD2, which converts cortisol to cortisone, was assessed by immunoblot, in models of prostate cancer, tissues from patients treated with enzalutamide and prostate tissues treated exogenously with enzalutamide. The effect of shRNA knockdown of the AMFR ubiquitin E3-ligase on 11βHSD2 protein expression and enzyme activity was assessed. Finally, the potential therapeutic effects of 11βHSD2 re-expression on enzalutamide resistance was assessed in xenograft models. Results: Enzalutamide impedes inactivation of cortisol to cortisone, thereby sustaining tumor cortisol concentrations, permitting GR stimulation and enzalutamide resistance. Impeded cortisol inactivation by enzalutamide occurs by way of 11β-HSD2 expression loss in models of prostate cancer, prostate tissues from enzalutamide-treated patients and fresh prostatic tissues treated exogenously with enzalutamide. AMFR mediates loss of 11β-HSD2, which otherwise inactivates cortisol. Remarkably, reinstatement of 11β-HSD2 expression, or AMFR loss, reverses enzalutamide resistance in mouse xenograft tumors. Conclusions: Together, these findings reveal a surprising metabolic mechanism of enzalutamide resistance that may be targeted with a strategy that circumvents a requirement for systemic GR ablation.

scholarly journals Aberrant corticosteroid metabolism in tumor cells enables GR takeover in enzalutamide resistant prostate cancer

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Jianneng Li ◽  
Mohammad Alyamani ◽  
Ao Zhang ◽  
Kai-Hsiung Chang ◽  
Michael Berk ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Glucocorticoid Receptor ◽  
Tumor Cells ◽  
Target Genes ◽  
Hydroxysteroid Dehydrogenase ◽  
Mouse Xenograft ◽  
Ubiquitin E3 Ligase ◽  
Metabolic Mechanism ◽  
Stimulation Of

Prostate cancer is driven by androgen stimulation of the androgen receptor (AR). The next-generation AR antagonist, enzalutamide, prolongs survival, but resistance and lethal disease eventually prevail. Emerging data suggest that the glucocorticoid receptor (GR) is upregulated in this context, stimulating expression of AR-target genes that permit continued growth despite AR blockade. However, countering this mechanism by administration of GR antagonists is problematic because GR is essential for life. We show that enzalutamide treatment in human models of prostate cancer and patient tissues is accompanied by a ubiquitin E3-ligase, AMFR, mediating loss of 11β-hydroxysteroid dehydrogenase-2 (11β-HSD2), which otherwise inactivates cortisol, sustaining tumor cortisol concentrations to stimulate GR and enzalutamide resistance. Remarkably, reinstatement of 11β-HSD2 expression, or AMFR loss, reverses enzalutamide resistance in mouse xenograft tumors. Together, these findings reveal a surprising metabolic mechanism of enzalutamide resistance that may be targeted with a strategy that circumvents a requirement for systemic GR ablation.

Modulating glucocorticoid receptor function in breast and prostate cancer

2018 ◽  
Author(s):  
E. Tonsing-Carter ◽  
T. Long ◽  
D.C. West ◽  
R. Harkless ◽  
D.N. Dolcen ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Glucocorticoid Receptor ◽  
Receptor Function ◽  
Breast And Prostate Cancer

scholarly journals Validating Anti-Infective Activity of Pleurotus Opuntiae via Standardization of Its Bioactive Mycoconstituents through Multimodal Biochemical Approach

Coatings ◽  
2021 ◽  
Vol 11 (4) ◽  
pp. 484
Author(s):  
Aprajita Tiwari Pandey ◽  
Ishan Pandey ◽  
Anurag Kanase ◽  
Amita Verma ◽  
Beatriz Garcia-Canibano ◽  
...  
Keyword(s):  
Bioactive Compounds ◽  
High Performance ◽  
Colorimetric Assay ◽  
Diffusion Method ◽  
Therapeutic Effects ◽  
Medication Regimen ◽  
Methanol Extracts ◽  
Retention Factors ◽  
Before And After ◽  
Solvent Systems

Mushrooms produce a variety of bioactive compounds that are known to have anti-pathogenic properties with safer and effective therapeutic effects in human disease prognosis. The antibacterial activity of ethanol and methanol extracts of Pleurotus opuntiae were checked against pathogenic microorganisms viz. Pseudomonas aeruginosa ATCC 27853, Proteus mirabilis NCIM 2300, Proteus vulgaris NCIM 5266, Serratia marcescens NCIM 2078, Shigella flexeneri NCIM 5265, Moraxella sp. NCIM 2795, Staphylococcus aureus ATCC 25923 by agar well diffusion method at different concentrations of the extracts. Minimum Inhibitory Concentration (MIC) and Minimum Bactericidal Concentration (MBC) of the extracts was determined by INT (Iodonitrotetrazolium chloride) colorimetric assay. Extracts were standardized by thin layer chromatography (TLC) in different solvent systems. The Retention factors (Rf) of different compounds were calculated by high performance TLC (HPTLC) fingerprinting at UV 254, 366, and 540 nm before and after derivatization. The ethanol and methanol extracts of P. opuntiae showed bactericidal activity against all the test pathogens at MIC values of 15.6 to 52.08 mg/mL and 20.81 to 52.08 mg/mL respectively. Whereas the MBC values for ethanol and methanol extract of P. opuntiae against all pathogens were recorded as 26.03 to 62.5 mg/mL and 125 mg/mL respectively. Preliminary mycochemical screening of both the extracts revealed high contents of bioactive compounds. Amongst all the solvent systems used in TLC, the best result was given by chloroform + hexane (8:2) which eluted out 5 different compounds (spots). HPTLC results revealed spots with different Rf values for all the 24 compounds present. Thus, it can be inferred from the present investigation that the mycoconstituents could be an alternative medication regimen and could play a role in new drug discoveries against different infections. Further, the antimicrobial components of these mushrooms can be transformed to bioengineered antimicrobial coatings for surfaces, drug and other hybrid systems for public health implications in combating persistent infections.

Hispidulin inhibits proliferation, migration, and invasion by promoting autophagy via regulation of PPARγ activation in prostate cancer cells and xenograft models

2020 ◽  
Author(s):  
Yuanyuan Wang ◽  
Shanqi Guo ◽  
Yingjie Jia ◽  
Xiaoyu Yu ◽  
Ruiyu Mou ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Flavonoid Compound ◽  
Migration And Invasion ◽  
Prostate Cancer Cells ◽  
Invasion And Migration ◽  
Beneficial Effects ◽  
Anticancer Properties ◽  
Xenograft Models ◽  
And Migration

ABSTRACT Prostate cancer (PCa) is one of the important factors of cancer deaths especially in the western countries. Hispidulin (4′,5,7-trihydroxy-6-methoxyflavone) is a phenolic flavonoid compound proved to possess anticancer properties, but its effects on PCa are left to be released. The aims of this study were to investigate the effects and the relative mechanisms of Hispidulin on PCa development. Hispidulin administration inhibited proliferation, invasion, and migration, while accelerated apoptosis in Du145 and VCaP cells, which was accompanied by PPARγ activation and autophagy enhancement. The beneficial effects of Hispidulin could be diminished by PPARγ inhibition. Besides, Hispidulin administration suppressed PCa tumorigenicity in Xenograft models, indicating the anticancer properties in vivo. Therefore, our work revealed that the anticancer properties of Hispidulin might be conferred by its activation on PPARγ and autophagy.

scholarly journals Dandelion Root and Lemongrass Extracts Induce Apoptosis, Enhance Chemotherapeutic Efficacy, and Reduce Tumour Xenograft Growth In Vivo in Prostate Cancer

2019 ◽  
Vol 2019 ◽  
pp. 1-12 ◽  
Author(s):  
Christopher Nguyen ◽  
Ali Mehaidli ◽  
Kiruthika Baskaran ◽  
Sahibjot Grewal ◽  
Alaina Pupulin ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Root Extract ◽  
Natural Health Products ◽  
Anticancer Efficacy ◽  
Adjuvant Therapies ◽  
Anticancer Effects ◽  
Health Products ◽  
Xenograft Models ◽  
Pharmaceutical Uses

Many conventional chemotherapies have indicated side effects due to a lack of treatment specificity and are thus not suitable for long-term usage. Natural health products are well-tolerated and safe for consumption, and some have pharmaceutical uses particularly for their anticancer effects. We have previously reported the anticancer efficacy of dandelion (Taraxacum officinale) root and lemongrass (Cymbopogon citratus) extracts. However, their efficacy on prostate cancer and their interactions with standard chemotherapeutics have not been studied to determine if they will be suitable for adjuvant therapies. If successful, these extracts could potentially be used in conjunction with chemotherapeutics to minimize the risk of drug-related toxicity and enhance the efficacy of the treatment. We have demonstrated that both dandelion root extract (DRE) and lemongrass extract (LGE) exhibit selective anticancer activity. Importantly, DRE and LGE addition to the chemotherapeutics taxol and mitoxantrone was determined to enhance the induction of apoptosis when compared to individual chemotherapy treatment alone. Further, DRE and LGE were able to significantly reduce the tumour burden in prostate cancer xenograft models when administered orally, while also being well-tolerated. Thus, the implementation of these well-tolerated extracts in adjuvant therapies could be a selective and efficacious approach to prostate cancer treatment.

148 Identification of prostate-restricted epithelial antigens for transgenic T cell adoptive therapy against prostate cancer

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A161-A161
Author(s):  
Diana DeLucia ◽  
Tiffany Pariva ◽  
Roland Strong ◽  
Owen Witte ◽  
John Lee
Keyword(s):  
Prostate Cancer ◽  
T Cells ◽  
T Cell ◽  
Single Cell ◽  
Cd8 T Cells ◽  
Adoptive Therapy ◽  
Mhc I ◽  
Epithelial Antigens ◽  
Ifn Γ ◽  
Stimulation Of

BackgroundIn advanced prostate cancer (PCa), progression to castration-resistant PCa (CRPC) is inevitable and novel therapies for CRPC are needed. Adoptive transfer of T cells targeting tumor antigens is a promising approach in the cancer field. Unfortunately, identifying antigens expressed exclusively in prostate tumor cells has been challenging. Since the prostate is not an essential organ, we alternatively selected prostate-restricted epithelial antigens (PREAs) expressed in both malignant and normal prostate tissue for transgenic T cell studies.MethodsRNA-seq data sets identifying genes enriched in PCa were cross-referenced with the NIH Genotype-Expression database to identify PREAs. Using a novel molecular immunology approach, select PREAs and major histocompatibility complex class I (MHC-I) molecules were co-expressed in HEK293F cells, from which MHC–peptide complexes were efficiently isolated. Peptides were eluted and sequenced by mass spectrometry. Peptide–MHC binding was validated with a T2 stabilization assay and peptide immunodominance was determined using an interferon-γ (IFN-γ) ELISpot assay following stimulation of healthy HLA-A2+ peripheral blood mononuclear cells (PBMC) with peptide pools. Following peptide stimulation, CD8+ T cells with peptide-specific T cell receptors (TCR) were enriched by peptide–MHC-I dextramer labeling and fluorescence activated cell sorting for single cell TCR α/β chain sequencing.ResultsWe identified 11 A2+ peptides (8 previously unpublished) from prostatic acid phosphatase (ACPP), solute carrier family 45 member 3 (SLC45A3), and NK3 homeobox 1 (NKX3.1) that bound to HLA-A2 with varying affinities. Extended culture stimulation of PBMC with peptide pools from each PREA, compared to the standard overnight culture, revealed a greater number of IFN-γ producing cells overall and a greater breadth of response across all the peptides. Antigen specific CD8+ T cells were detectable at low frequencies in both male and female healthy PBMC for 7 of the 11 peptides. Dextramer-sorted antigen-specific cells were used for single-cell paired TCR αβ sequencing and transgenic T cell development.ConclusionsThrough this work we identified HLA-A2-presented antigenic peptides from the PREAs ACPP, SLC45A3, and NKX3.1 that can induce the expansion of IFN-γ producing CD8+ T cells. Through peptide–MHC-I dextramer labeling, we isolated PREA-specific CD8+ T cells and characterized TCR αβ sequences with potential anti-tumor functionality. Our results highlight a rapid and directed platform for the development of MHC-I-restricted transgenic CD8+ T cells targeting lineage-specific proteins expressed in prostate epithelia for adoptive therapy of advanced PCa.

Paradoxical Stimulation of Prolactin Secretion by L–Dopa in Metastatic Prostate Cancer and Its Possible Role in Prostate–Cancer–Related Hyperprolactinemia

2000 ◽  
Vol 37 (5) ◽  
pp. 569-572 ◽  
Author(s):  
Paolo Lissoni ◽  
Mario Mandalà ◽  
Franco Rovelli ◽  
Marina Casu ◽  
Francesco Rocco ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Metastatic Prostate Cancer ◽  
Prolactin Secretion ◽  
Stimulation Of

scholarly journals The intriguing role of fibroblasts and c-Jun in the chemo-preventive and therapeutic effect of finasteride on xenograft models of prostate cancer

2015 ◽  
Vol 0 (0) ◽  
pp. 0
Author(s):  
Yi-Nong Niu ◽  
Kai Wang ◽  
Song Jin ◽  
Dong-Dong Fan ◽  
Ming-Shuai Wang ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Therapeutic Effect ◽  
Xenograft Models
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