scholarly journals The Steroidogenic Enzyme AKR1C3 Regulates Stability of the Ubiquitin Ligase Siah2 in Prostate Cancer Cells

2015 ◽  
Vol 290 (34) ◽  
pp. 20865-20879 ◽  
Author(s):  
Lingling Fan ◽  
Guihong Peng ◽  
Arif Hussain ◽  
Ladan Fazli ◽  
Emma Guns ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Growth ◽  
Cancer Cells ◽  
Ubiquitin Ligase ◽  
Castration Resistant Prostate Cancer ◽  
Prostate Cancer Cells ◽  
Cancer Cell Growth ◽  
Protein Levels ◽  
Castration Resistant

Re-activation of androgen receptor (AR) activity is the main driver for development of castration-resistant prostate cancer. We previously reported that the ubiquitin ligase Siah2 enhanced AR transcriptional activity and prostate cancer cell growth. Among the genes we found to be regulated by Siah2 was AKR1C3, which encodes a key androgen biosynthetic enzyme implicated in castration-resistant prostate cancer development. Here, we found that Siah2 inhibition in CWR22Rv1 prostate cancer cells decreased AKR1C3 expression as well as intracellular androgen levels, concomitant with inhibition of cell growth in vitro and in orthotopic prostate tumors. Re-expression of either wild-type or catalytically inactive forms of AKR1C3 partially rescued AR activity and growth defects in Siah2 knockdown cells, suggesting a nonenzymatic role for AKR1C3 in these outcomes. Unexpectedly, AKR1C3 re-expression in Siah2 knockdown cells elevated Siah2 protein levels, whereas AKR1C3 knockdown had the opposite effect. We further found that AKR1C3 can bind Siah2 and inhibit its self-ubiquitination and degradation, thereby increasing Siah2 protein levels. We observed parallel expression of Siah2 and AKR1C3 in human prostate cancer tissues. Collectively, our findings identify a new role for AKR1C3 in regulating Siah2 stability and thus enhancing Siah2-dependent regulation of AR activity in prostate cancer cells.

scholarly journals Identification of genes required for enzalutamide resistance in castration-resistant prostate cancer cells in vitro

2020 ◽  
pp. molcanther.0244.2020
Author(s):  
Sarah E Kohrt ◽  
Wisam N Awadallah ◽  
Robert A Phillips ◽  
Thomas C. Case ◽  
Renjie Jin ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Cells ◽  
Castration Resistant Prostate Cancer ◽  
Prostate Cancer Cells ◽  
Castration Resistant

Statin inhibits the proliferation of human castration-resistant prostate cancer cells by controlling NFkB-LIN28B-let7 miRNA signaling pathway.

2017 ◽  
Vol 35 (6_suppl) ◽  
pp. 269-269 ◽  
Author(s):  
Chang Wook Jeong ◽  
Ja Hyeon Ku ◽  
Hyeon Hoe Kim ◽  
Cheol Kwak ◽  
Minyong Kang
Keyword(s):  
Prostate Cancer ◽  
Cell Growth ◽  
Cancer Cells ◽  
Signaling Pathway ◽  
Molecular Mechanism ◽  
Cell Lines ◽  
Castration Resistant Prostate Cancer ◽  
Prostate Cancer Cells ◽  
Simvastatin Treatment ◽  
Castration Resistant

269 Background: Although statin use has been associated with improved outcomes in prostate cancer, the molecular mechanism of this action is still unclear. Based on previous findings, we aimed to investigate the potential role of NFkB-Lin28B-let7 miRNA signaling pathway in human prostate cancer, particularly, castration-resistant prostate cancer (CRPC) cells, as a molecular mechanism of statin effect. Methods: Various human CRPC cell lines (PC3, DU145, 22Rv1, C42B) were used in this study. Proliferation of prostate cancer cells were measured by MTT assay and colony formation assay. Lin28B and NF-κB expression were controlled by siRNA transfection and the expression on Lin28 and let-7 miRNA were quantitated using RT-PCR and western blotting. Results: Notably, simvastatin treatment on various CRPC cell lines decreased cell viabilities in a dose dependent manner. It also significantly inhibited cell growth in clonogenic assay. In these CRPC cells, LIN28 gene was highly expressed in mRNa and protein levels. Conversely, micro RNA (miRNA) expressions of let7 family were remarkably downregulated in CRPC cells. By simvastatin treatment, mRNA and protein level of Lin28B were decreased, while let7 miRNA expressions were restored, which was the key finding of the current study. Considering NFkB is the upstream molecule of Lin28B, we found that the double treatment of statin and NF-κB inhibitor (CAPE) resulted in decreased cell viability, Lin28B and cyclin D1 expression, synergistically. Of note, let-7 miRNA levels were restored after simvastatin treatment, and further increased their expression levels by CAPE double treatment. In order to confirm this mechanistic clue, we specifically inhibited Lin28B and NF-κB genes, respectively, resulting in increased cell apoptosis signaling in the Lin28b or NF-κB knock down cells by combined treatment with simvastatin. Conclusions: In conclusion, simvastatin inhibited the cell growth of various human CRPC cell lines by controlling NFkB-LIN28B-let7 miRNA signaling pathway, and therefore; concurrent NF-κB inhibition with simvastatin treatment induce the synergistic anti-cancer effects in human CRPC cells.

scholarly journals IL1B loss is associated with increased AR activity in castration-resistant prostate cancer

2021 ◽  
Author(s):  
Wisam N. Awadallah ◽  
Jagpreet S. Nanda ◽  
Sarah E. Kohrt ◽  
Magdalena M Grabowska
Keyword(s):  
Gene Expression ◽  
Prostate Cancer ◽  
Cancer Cells ◽  
Marker Gene ◽  
Neuroendocrine Differentiation ◽  
Castration Resistant Prostate Cancer ◽  
Prostate Cancer Cells ◽  
Castration Resistant ◽  
Expression And Activity

Castration-resistant prostate cancer represents a continuum of phenotypes, including tumors with high levels of androgen receptor (AR) expression and activity and those which do not express AR and rely on alternative pathways for survival. The process by which AR-positive prostate cancer cells and tumors lose AR expression and acquire neuroendocrine features is referred to as neuroendocrine differentiation. Numerous therapies and exposures have been demonstrated to induce neuroendocrine differentiation in vitro, including the pro-inflammatory cytokine, interleukin 1 beta (IL-1β), encoded by the gene IL1B. The purpose of our studies was to determine the relationship between the expression and activity of AR in relationship to IL-1β and IL1B in prostate cancer. We performed analysis of de-identified human clinical data and generated prostate cancer cell lines with overexpression or knockout of IL1B. In primary prostate cancer, higher expression of IL1B predicts longer time to biochemical recurrence. In metastatic castration-resistant prostate cancer, IL1B expression is decreased and inversely correlates with AR and AR-target gene expression and AR activity, while positively correlating with the neuroendocrine prostate cancer (NEPC) score and neuroendocrine marker gene expression. In vitro, we report that AR-positive castration-resistant prostate cancer cells (C4-2B, 22Rv1) secrete IL-1β, and knockout of IL1B in these cells results in increased AR activity, in the presence and absence of dihydrotestosterone (DHT). Importantly, knockout of IL1B prevented AR attrition during androgen-deprivation. Taken together, our studies demonstrate that loss of IL1B in AR-positive castration-resistant prostate cancer cells can increase and maintain AR activity in the absence of androgens, suggesting another potential mechanism of high AR activity in castration-resistant prostate cancer.

S100A3 Suppression Inhibits In Vitro and In Vivo Tumor Growth and Invasion of Human Castration-resistant Prostate Cancer Cells

Urology ◽  
2015 ◽  
Vol 85 (1) ◽  
pp. 273.e9-273.e15 ◽  
Author(s):  
Minyong Kang ◽  
Hye Sun Lee ◽  
Young Ju Lee ◽  
Woo Suk Choi ◽  
Yong Hyun Park ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Tumor Growth ◽  
Cancer Cells ◽  
Castration Resistant Prostate Cancer ◽  
Prostate Cancer Cells ◽  
Castration Resistant ◽  
Tumor Growth And Invasion

scholarly journals Synthesis and Anti-Proliferative Effects of Quercetin Derivatives

2015 ◽  
Vol 10 (12) ◽  
pp. 1934578X1501001 ◽  
Author(s):  
Sami M.R. Al-Jabban ◽  
Xiaojie Zhang ◽  
Guanglin Chen ◽  
Ermias Addo Mekuria ◽  
Liva Harinantenaina Rakotondraibe ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Cells ◽  
Chemical Reactivity ◽  
Biological Data ◽  
Flavonoid Compound ◽  
Castration Resistant Prostate Cancer ◽  
Prostate Cancer Cells ◽  
Quercetin Derivatives ◽  
Castration Resistant

Prostate cancer is the most common diagnosed invasive cancer in American men and is the second leading cause of cancer-related deaths. Although there are several therapies successful in treating early, localized stage prostate cancer, current treatment of advanced metastatic castration-resistant prostate cancer remains ineffective due to inevitable progression of resistance to first-line treatment with docetaxel. The natural product quercetin (3,3′,4′,5,7-pentahydroxyflavone), a flavonoid compound ubiquitous in dietary plants, possesses evidenced potential in treating advanced metastatic castration-resistant prostate cancer. However, its poor bioavailability and moderate potency hinder its advancement into clinical therapy. In order to engineer quercetin derivatives with improved potency and pharmacokinetic profiles for the treatment of advanced metastatic prostate cancer, we started this study with creating a small library of alkylated derivatives of quercetin for in vitro evaluation. The biological data and chemical reactivity of quercetin and its derivatives reported in literature directed us to design 3,4′,7- O-trialkylquercetins as our first batch of targets. Consequently, nine 3,4′,7- O-trialkylquercetins, together with four 3,7- O-dialkylquercetins, four 3,3′,4′,7-tetraalkylquercetins, and one 3,3′,4′- O-trialkylquercetin, were prepared by one step O-alkylation of commercially available quercetin mediated by potassium carbonate. Their structures were determined by 1D and 2D NMR data, and HRMS. Their anti-proliferative activities towards both androgen-refractory and androgen-sensitive prostate cancer cells were evaluated using WST-1 cell proliferation assay. The acquired structure-activity relationships indicate that 3,7- O-dialkylquercetins rather than 3,4′,7- O-trialkylquercetins were much more potent than quercetin towards prostate cancer cells.

Targeting Nrf2-antioxidant signaling reverses acquired cabazitaxel resistance in prostate cancer cells

2021 ◽  
Author(s):  
Satoshi Endo ◽  
Mina Kawai ◽  
Manami Hoshi ◽  
Jin Segawa ◽  
Mei Fujita ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Cells ◽  
Good Prognosis ◽  
Nuclear Accumulation ◽  
Related Factor ◽  
Castration Resistant Prostate Cancer ◽  
Prostate Cancer Cells ◽  
Protein Levels ◽  
Castration Resistant

Abstract Prostate cancer is known to have a relatively good prognosis, but long-term hormone therapy can lead to castration-resistant prostate cancer (CRPC). Cabazitaxel, a second-generation taxane, has been used for the CRPC treatment, but its tolerance is an urgent problem to be solved. In this study, to elucidate the acquisition mechanism of the cabazitaxel-resistance, we established cabazitaxel-resistant prostate cancer 22Rv1 (Cab-R) cells, which exhibited approximately 7-fold higher LD50 against cabazitaxel than the parental 22Rv1 cells. Cab-R cells showed marked increases in nuclear accumulation of NF-E2 related factor 2 (Nrf2) and expression of Nrf2-inducible antioxidant enzymes compared to 22Rv1 cells, suggesting that Nrf2 signaling is homeostatically activated in Cab-R cells. The cabazitaxel sensitivity of Cab-R cells was enhanced by silencing of Nrf2, and that of 22Rv1 cells was reduced by activation of Nrf2. Halofuginone (HF) has been recently identified as a potent Nrf2 synthetic inhibitor, and its treatment of Cab-R cells not only suppressed the Nrf2 signaling by decreasing both nuclear and cytosolic Nrf2 protein levels, but also significantly augmented the cabazitaxel sensitivity. Thus, inhibition of Nrf2 signaling may be effective in overcoming the cabazitaxel resistance in prostate cancer cells.

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