Overexpression of SOCS3 mediated by adenovirus vector in mouse and human castration-resistant prostate cancer cells increases the sensitivity to NK cells in vitro and in vivo

Introduction. Radiotherapy is the mainstay in the treatment of prostate cancer. However, significant radioresistance of castration-resistant prostate cancer (CRPC) cells constitutes a main obstacle in the treatment of this disease. By using bioinformatic data mining methods, LOXL2 was found to be upregulated in both androgen-independent prostate cancer cell lines and radioresistant tumor samples collected from patients with prostate cancer. We speculate that LOXL2 may play an important role in the radioresistance of CRPC cells. Methods. The effect of LOXL2 knockdown on the radiosensitivity of androgen-independent prostate cancer cells lines was measured by the clonogenic assay and xenograft tumor experiments under in vitro and in vivo conditions, respectively. In studies on the mechanism, we focused on the EMT phenotype changes and cell apoptosis changes induced by LOXL2 knockdown in DU145 cells. The protein levels of three EMT biomarkers, namely, E-cadherin, vimentin, and N-cadherin, were measured by western blotting and immunohistochemical staining. Cell apoptosis after irradiation was measured by flow cytometry and caspase-3 activity assay. Salvage experiment was also conducted to confirm the possible role of EMT in the radiosensitization effect of LOXL2 knockdown in CRPC cells. Results. LOXL2 knockdown in CRPC cells enhanced cellular radiosensitivity under both in vitro and in vivo conditions. A significant reversal of EMT was observed in LOXL2-silenced DU145 cells. Cell apoptosis after irradiation was significantly enhanced by LOXL2 knockdown in DU145 cells. Results from the salvage experiment confirmed the key role of EMT process reversal in the radiosensitization effect of LOXL2 knockdown in DU145 cells. Conclusions. LOXL2 plays an important role in the development of cellular radioresistance in CRPC cells. Targeting LOXL2 may be a rational avenue to overcome radioresistance in CRPC cells. A LOXL2-targeting strategy for CRPC treatment warrants detailed investigation in the future.

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

Molecular Cancer Therapeutics ◽

10.1158/1535-7163.mct-20-0244 ◽

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

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Cotargeting Polo-Like Kinase 1 and the Wnt/β-Catenin Signaling Pathway in Castration-Resistant Prostate Cancer

Molecular and Cellular Biology ◽

10.1128/mcb.00825-15 ◽

2015 ◽

Vol 35 (24) ◽

pp. 4185-4198 ◽

Cited By ~ 14

Author(s):

Jie Li ◽

Anju Karki ◽

Kurt B. Hodges ◽

Nihal Ahmad ◽

Amina Zoubeidi ◽

...

Keyword(s):

Prostate Cancer ◽

Cancer Cells ◽

Signaling Pathway ◽

Glycogen Synthase ◽

Therapeutic Option ◽

Negative Regulator ◽

Castration Resistant Prostate Cancer ◽

Prostate Cancer Cells ◽

Castration Resistant

The Wnt/β-catenin signaling pathway has been identified as one of the predominantly upregulated pathways in castration-resistant prostate cancer (CRPC). However, whether targeting the β-catenin pathway will prove effective as a CRPC treatment remains unknown. Polo-like kinase 1 (Plk1) is a critical regulator in many cell cycle events, and its level is significantly elevated upon castration of mice carrying xenograft prostate tumors. Indeed, inhibition of Plk1 has been shown to inhibit tumor growth in severalin vivostudies. Here, we show that Plk1 is a negative regulator of Wnt/β-catenin signaling. Plk1 inhibition or depletion enhances the level of cytosolic and nuclear β-catenin in human prostate cancer cells. Furthermore, inhibition of Wnt/β-catenin signaling significantly potentiates the antineoplastic activity of the Plk1 inhibitor BI2536 in both cultured prostate cancer cells and CRPC xenograft tumors. Mechanistically, axin2, a negative regulator of the β-catenin pathway, serves as a substrate of Plk1, and Plk1 phosphorylation of axin2 facilitates the degradation of β-catenin by enhancing binding between glycogen synthase kinase 3β (GSK3β) and β-catenin. Plk1-phosphorylated axin2 also exhibits resistance to Cdc20-mediated degradation. Overall, this study identifies a novel Plk1-Wnt signaling axis in prostate cancer, offering a promising new therapeutic option to treat CRPC.

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

10.1101/2021.08.31.458406 ◽

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.

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Synthesis and Anti-Proliferative Effects of Quercetin Derivatives

Natural Product Communications ◽

10.1177/1934578x1501001225 ◽

2015 ◽

Vol 10 (12) ◽

pp. 1934578X1501001 ◽

Cited By ~ 4

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.

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Abstract 3147: Adipocytes affect castration-resistant prostate cancer cells in resistance to cytotoxic action of NK cells through alterations of pd-l1/nkg2d ligand levels

10.1158/1538-7445.am2018-3147 ◽

2018 ◽

Cited By ~ 1

Author(s):

Lijun Xu ◽

Mingjing Shen ◽

Xiaodong Chen ◽

Rongying Zhu ◽

Dong-rong Yang ◽

...

Keyword(s):

Prostate Cancer ◽

Nk Cells ◽

Cancer Cells ◽

Cytotoxic Action ◽

Nkg2d Ligand ◽

Castration Resistant Prostate Cancer ◽

Prostate Cancer Cells ◽

Castration Resistant

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

Journal of Biological Chemistry ◽

10.1074/jbc.m115.662155 ◽

2015 ◽

Vol 290 (34) ◽

pp. 20865-20879 ◽

Cited By ~ 15

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.

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