Nuclear Kaiso Indicates Aggressive Prostate Cancers and Promotes Migration and Invasiveness of Prostate Cancer Cells

Abstract Prostate cancers respond to treatments that suppress androgen receptor (AR) function, with bicalutamide, flutamide, and cyproterone acetate (CPA) being AR antagonists in clinical use. As CPA has substantial agonist activity, it was examined to identify AR coactivator/corepressor interactions that may mediate androgen-stimulated prostate cancer growth. The CPA-liganded AR was coactivated by steroid receptor coactivator-1 (SRC-1) but did not mediate N-C terminal interactions or recruit β-catenin, indicating a nonagonist conformation. Nonetheless, CPA did not enhance AR interaction with nuclear receptor corepressor, whereas the AR antagonist RU486 (mifepristone) strongly stimulated AR-nuclear receptor corepressor binding. The role of coactivators was further assessed with a T877A AR mutation, found in LNCaP prostate cancer cells, which converts hydroxyflutamide (HF, the active flutamide metabolite) into an agonist that stimulates LNCaP cell growth. The HF and CPA-liganded T877A ARs were coactivated by SRC-1, but only the HF-liganded T877A AR was coactivated by β-catenin. L-39, a novel AR antagonist that transcriptionally activates the T877A AR, but still inhibits LNCaP growth, similarly mediated recruitment of SRC-1 and not β-catenin. In contrast, β-catenin coactivated a bicalutamide-responsive mutant AR (W741C) isolated from a bicalutamide-stimulated LNCaP subline, further implicating β-catenin recruitment in AR-stimulated growth. Androgen-stimulated prostate-specific antigen gene expression in LNCaP cells could be modulated by β-catenin, and endogenous c-myc expression was repressed by dihydrotestosterone, but not CPA. These results indicate that interactions between AR and β-catenin contribute to prostate cell growth in vivo, although specific growth promoting genes positively regulated by AR recruitment of β-catenin remain to be identified.

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Identification of a small-molecule inhibitor of Stat5a/b through structure-based screen for therapy development for prostate cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2011.29.7_suppl.17 ◽

2011 ◽

Vol 29 (7_suppl) ◽

pp. 17-17

Author(s):

Z. Liao ◽

L. Gu ◽

F. Shen ◽

A. Dagvadorj ◽

S. Gupta ◽

...

Keyword(s):

Prostate Cancer ◽

Cancer Cells ◽

Small Molecule ◽

Nuclear Translocation ◽

Human Prostate ◽

Prostate Cancer Cells ◽

Castration Resistant ◽

Molecule Inhibitor ◽

Prostate Cancers

17 Background: There are no effective treatments for metastatic or castration resistant prostate cancer. We have shown that transcription factor Stat5a/b is constitutively active in high-grade prostate cancer, but not in normal human prostate epithelium. Stat5a/b is active in 95% of clinical castration resistant prostate cancers, and the expression of active Stat5a/b in primary prostate cancer predicts early disease recurrence. Stat5a/b is critical for the viability of prostate cancer cells in vitro and for growth of prostate xenograft tumors in nude mice. Stat5a/b synergizes with androgen receptor (AR) and Stat5a/b promotes metastatic behavior of human prostate cancer cells in vitro and in vivo. Here, we hypothesize that Stat5a/b is a molecular target for rational drug design for prostate cancer. Methods: We identified a small- molecule inhibitor of Stat5a/b dimerization by structure-based virtual screen from a database of 30 million chemical structures. The efficacy of the Stat5a/b inhibitor was determined by reporter gene assays, dimerization by co-immunoprecipitations, nuclear translocation by cytochemistry and binding to DNA by EMSA. Cell viability was analyzed by MTT assay. Results: The novel Stat5a/b inhibitor IST5-002 inhibited transcriptional activity of Stat5a/b at IC50 of 1.5 μ M for Stat5a and 3.5 μ M for Stat5b, but not of Stat3 in prostate cancer cells. IST5-002 inhibited dimerization, nuclear translocation, and binding of Stat5a/b to the Stat5 DNA consensus sequence. Furthermore, IST5-002 inhibited expression of Stat5a/b target gene cyclin D1, and induced massive apoptosis of DU145, CWR22Rv1 and LNCaP human prostate cancer cells. IST5-002 blocked prostate cancer xenograft tumor growth in nude mice and induced death in clinical prostate cancers ex vivo in 3D organ cultures. Conclusions: We have identified a small molecule Stat5a/b inhibitor IST5-002 for therapy development for prostate cancer. Future work will focus on chemical modifications of IST5-002 to achieve IC50 below 1 μ M and oral administration. No significant financial relationships to disclose.

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Cold Atmospheric Plasma Selectively Induces G0/G1 Cell Cycle Arrest and Apoptosis in AR-Independent Prostate Cancer Cells

10.21203/rs.3.rs-49986/v1 ◽

2020 ◽

Author(s):

Meng Ning ◽

Zhifa Zhang ◽

Lihui Yu ◽

Peiyu Han ◽

xiaofeng Dai

Keyword(s):

Prostate Cancer ◽

Cell Cycle ◽

Androgen Receptor ◽

Cancer Cells ◽

Atmospheric Plasma ◽

Prostate Cancer Cells ◽

Cold Atmospheric Plasma ◽

Prostate Cancers ◽

And Migration ◽

Physical Plasma

Abstract BackgroundAndrogen receptor-independent prostate cancers do not respond to androgen blockage therapies and suffer from high recurrence rate. We aim to contribute to the establishment of novel therapeutic approaches against such malignancies.Methods We examined whether and how cold atmospheric plasma delivers selectivity against AR-independent prostate cancers using human normal epithelial prostatic cells PNT1A and AR-negative DU145 prostate cancer cells.ResultsWe show that cold atmospheric plasma could selectively halt cell proliferation and migration in androgen receptor-independent cells as a result of induced cell apoptosis and G0/G1 stage cell cycle arrest, and such outcomes were achieved through modulations on the MAPK and NF-kB pathways in response to physical plasma induced intracellular redox level. ConclusionOur study reports cold atmospheric plasma induced reduction on the proliferation and migration of androgen receptor-independent prostate cancer cells that offers novel therapeutic insights on the treatment of such cancers, and provides the first evidence on physical plasma induced cell cycle G0/G1 stage arrest that warrants the exploration on the synergistic use of cold atmospheric plasma and drugs such as chemotherapies in eradicating such cancer cells.

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Novel biomarker of specific castration-resistant prostate cancer (CRPC) by exploring the proteome analysis.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.6_suppl.247 ◽

2017 ◽

Vol 35 (6_suppl) ◽

pp. 247-247 ◽

Cited By ~ 1

Author(s):

Hiroji Uemura ◽

Noriaki Arakawa ◽

Yusuke Itoh ◽

Takashi Kawahara ◽

Yasuhide Miyoshi ◽

...

Keyword(s):

Prostate Cancer ◽

Cancer Cells ◽

Proteome Analysis ◽

Human Prostate ◽

Castration Resistant Prostate Cancer ◽

Prostate Cancer Cells ◽

Prostate Hyperplasia ◽

Castration Resistant ◽

Significant Difference ◽

Prostate Cancers

247 Background: It is well known that prostate specific antigen (PSA) level has no reliable correlation with pathological malignancy of prostate cancer and is not a predictor for the development of castration resistant prostate cancer (CRPC). The aim of this study is to explore novel biomarkers to predict the development of CRPC by using proteomics from secreted proteins from human prostate cancer cells. Methods: The proteins secreted from 6 prostate cancers in culture medium were analyzed and compared with 8 other cancer cells including renal and urothelial cancers using LTQ Orbitrap mass spectrometer. With the focus on high tissue specificity, the candidate biomarker proteins were then identified through analysis of gene expressions in proteins common to human prostate cancers by real time qPCR. Next, a system to measure the identified mouse monoclonal antibodies against the focused proteins was established. Finally, serum levels of these proteins from 33 patients with benign prostate hyperplasia (BPH), 31 with untreated prostate cancer (PCa) and 35 with CRPC, were measured. Results: The proteome analysis identified 12 candidates of secreted cell membrane proteins as new biomarkers. The proteome analysis indicated that not only matured GDF15, but pro-peptide as well as fragments (GDDP) are released from prostate cancer cells. Patients’ serum was analyzed for matured and pro-peptide GDF15 using ELISA and immunoprecipitation-MRM mass spectrometry. The results showed that the serum level of GDDP-1, one of the processing forms of GDDP, was significantly higher in CRPC than those in BPH and untreated PCa (P < 0.01). ROC analysis also showed that the AUC of GDDP-1(0.86) was higher than that of matured GDF15 (0.76). When the cutoff value of GDDP-1 was set at 4.0 ng/mL, there was a significant difference of overall survival (OS) in CRPC patients between those with more than 4.0 ng/mL compared to less than 4.0 ng/mL of GDDP-1, whereas there was no significant difference of OS measurable by PSA in CRPC patients. These data suggest that GDDP-1 may be a novel biomarker for CRPC. Conclusions: GDDP-1 shows potential as a novel biomarker for CRPC.

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Ceramide Regulates Anti-Tumor Mechanisms of Erianin in Androgen-Sensitive and Castration-Resistant Prostate Cancers

Frontiers in Oncology ◽

10.3389/fonc.2021.738078 ◽

2021 ◽

Vol 11 ◽

Author(s):

I Gusti Md Gde Surya C. Trapika ◽

Xin Tracy Liu ◽

Long Hoa Chung ◽

Felcia Lai ◽

Chanlu Xie ◽

...

Keyword(s):

Prostate Cancer ◽

Cancer Cells ◽

Ceramide Synthase ◽

Castration Resistant Prostate Cancer ◽

Prostate Cancer Cells ◽

Ceramide Level ◽

Novel Treatments ◽

Castration Resistant ◽

M Phase ◽

Prostate Cancers

Prostate cancer is the second most prevalent malignancy worldwide. In the early stages, the development of prostate cancer is dependent on androgens. Over time with androgen deprivation therapy, 20% of prostate cancers progress to a castration-resistant form. Novel treatments for prostate cancers are still urgently needed. Erianin is a plant-derived bibenzyl compound. We report herein that erianin exhibits anti-tumor effects in androgen-sensitive and castration-resistant prostate cancer cells through different mechanisms. Erianin induces endoplasmic reticulum stress-associated apoptosis in androgen-sensitive prostate cancer cells. It also triggers pro-survival autophagic responses, as inhibition of autophagy predisposes to apoptosis. In contrast, erianin fails to induce apoptosis in castration-resistant prostate cancer cells. Instead, it results in cell cycle arrest at the M phase. Mechanistically, C16 ceramide dictates differential responses of androgen-sensitive and castration-resistant prostate cancer cells to erianin. Erianin elevates C16 ceramide level in androgen-sensitive but not castration-resistant prostate cancer cells. Overexpression of ceramide synthase 5 that specifically produces C16 ceramide enables erianin to induce apoptosis in castration-resistant prostate cancer cells. Our study provides both experimental evidence and mechanistic data showing that erianin is a potential treatment option for prostate cancers.

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A novel acylglycerol kinase that produces lysophosphatidic acid modulates cross talk with EGFR in prostate cancer cells

The Journal of Cell Biology ◽

10.1083/jcb.200407123 ◽

2005 ◽

Vol 169 (5) ◽

pp. 801-811 ◽

Cited By ~ 125

Author(s):

Meryem Bektas ◽

Shawn G. Payne ◽

Hong Liu ◽

Sravan Goparaju ◽

Sheldon Milstien ◽

...

Keyword(s):

Prostate Cancer ◽

Cancer Cells ◽

Lysophosphatidic Acid ◽

Egf Receptor ◽

Subcellular Fractionation ◽

Prostate Cancer Cells ◽

Normal Prostate ◽

Lipid Kinase ◽

Acylglycerol Kinase ◽

Prostate Cancers

The bioactive phospholipids, lysophosphatidic acid (LPA) and phosphatidic acid (PA), regulate pivotal processes related to the pathogenesis of cancer. Here, we report characterization of a novel lipid kinase, designated acylglycerol kinase (AGK), that phosphorylates monoacylglycerol and diacylglycerol to form LPA and PA, respectively. Confocal microscopy and subcellular fractionation suggest that AGK is localized to the mitochondria. AGK expression was up-regulated in prostate cancers compared with normal prostate tissues from the same patient. Expression of AGK in PC-3 prostate cancer cells markedly increased formation and secretion of LPA. This increase resulted in concomitant transactivation of the EGF receptor and sustained activation of extracellular signal related kinase (ERK) 1/2, culminating in enhanced cell proliferation. AGK expression also increased migratory responses. Conversely, down-regulating expression of endogenous AGK inhibited EGF- but not LPA-induced ERK1/2 activation and progression through the S phase of the cell cycle. Hence, AGK can amplify EGF signaling pathways and may play an important role in the pathophysiology of prostate cancer.

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Ultra-effective photothermal therapy for prostate cancer cells using dual aptamer-modified gold nanostars

Journal of Materials Chemistry B ◽

10.1039/c4tb00643g ◽

2014 ◽

Vol 2 (30) ◽

pp. 4862-4867 ◽

Cited By ~ 28

Author(s):

Hunho Jo ◽

Hyungjun Youn ◽

Seonghwan Lee ◽

Changill Ban

Keyword(s):

Prostate Cancer ◽

Cancer Cells ◽

Photothermal Therapy ◽

Prostate Cancer Cells ◽

Gold Nanostars ◽

Prostate Cancers ◽

Disease Specific

A novel general platform for disease-specific photothermal therapy. This is the first demonstration of gold nanostars with tremendous efficiency and impressive selectivity for the targeted cancer, particularly the simultaneous targeting of PSMA(+) and PSMA(−) prostate cancers.

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6-Thioguanine and Its Analogs Promote Apoptosis of Castration-Resistant Prostate Cancer Cells in a BRCA2-Dependent Manner

Cancers ◽

10.3390/cancers11070945 ◽

2019 ◽

Vol 11 (7) ◽

pp. 945 ◽

Cited By ~ 1

Author(s):

Luna Laera ◽

Nicoletta Guaragnella ◽

Sergio Giannattasio ◽

Loredana Moro

Keyword(s):

Prostate Cancer ◽

Cell Proliferation ◽

Cancer Cells ◽

Breast Cancer Susceptibility Gene ◽

Dependent Manner ◽

Castration Resistant Prostate Cancer ◽

Prostate Cancer Cells ◽

Normal Prostate ◽

Castration Resistant ◽

Prostate Cancers

Background: Mutations in the oncosuppressor gene BReast CAncer susceptibility gene 2 (BRCA2) predispose to aggressive forms of prostate cancer which show poor response to taxane-based therapy, the standard treatment for castration-resistant, aggressive prostate cancer. Herein, we addressed the question whether changes in BRCA2 expression, a potential surrogate marker for BRCA2 activity, may affect the response of castration-resistant prostate cancer cells to 6-thioguanine (6-TG), a thiopurine used in the treatment of haematological malignancies. Methods: Yeast, normal prostate cells and castration-resistant prostate cancer cells were treated with 6-TG or its analogues, in presence or absence of paclitaxel, or with olaparib, a poly-(ADP-ribose) polymerase (PARP) inhibitor currently in clinical trials for treatment of metastatic castration-resistant prostate cancer, and cell proliferation, apoptosis and androgen receptor (AR) levels were measured. Results: 6-TG inhibited cell proliferation in yeast, normal and castration-resistant prostate cancer cells but promoted apoptosis only in cancer cells. Suppression of BRCA2 expression by siRNA or shRNA increased the sensitivity to 6-TG- and olaparib-induced apoptosis but did not affect cancer cell response to taxane. Intriguingly, 6-TG reduced AR expression levels independently on BRCA2 expression. Instead, olaparib decreased AR levels only in BRCA2-knockdown prostate cancer cells. Notably, overexpression of BRCA2 resulted in resistance of castration-resistant prostate cancer cells to 6-TG-, taxane- and olaparib-based treatment but promoted sensitivity to apoptosis induced by 2-amino-6-bromopurine and 2,6–dithiopurine, two 6-TG analogues. Conclusions: Our results provide a pre-clinical rationale for the use of 6-TG in the treatment of BRCA2-deficient castration-resistant prostate cancers, and of certain 6-TG analogues for treatment of BRCA2-proficient prostate cancers.

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Fatty Acid Inhibition Sensitizes Androgen-Dependent and -Independent Prostate Cancer to Radiotherapy via FASN/NF-κB Pathway

Scientific Reports ◽

10.1038/s41598-019-49486-2 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 8

Author(s):

Hui-Yen Chuang ◽

Yen-Po Lee ◽

Wei-Chan Lin ◽

Yi-Hsien Lin ◽

Jeng-Jong Hwang

Keyword(s):

Prostate Cancer ◽

Fatty Acid ◽

Cancer Cells ◽

Fatty Acid Synthase ◽

S Phase ◽

Prostate Cancer Cells ◽

Radiation Induced ◽

Prostate Cancers ◽

Fatty Acid Inhibition ◽

Phase Population

Abstract Elevated fatty acid synthase (FASN) has been reported in both androgen-dependent and -independent prostate cancers. Conventional treatment for prostate cancer is radiotherapy (RT); however, the following radiation-induced radioresistance often causes treatment failure. Upstream proteins of FASN such as Akt and NF-κB are found increased in the radioresistant prostate cancer cells. Nevertheless, whether inhibition of FASN could improve RT outcomes and reverse radiosensitivity of prostate cancer cells is still unknown. Here, we hypothesised that orlistat, a FASN inhibitor, could improve RT outcomes in prostate cancer. Orlistat treatment significantly reduced the S phase population in both androgen-dependent and -independent prostate cancer cells. Combination of orlistat and RT significantly decreased NF-κB activity and related downstream proteins in both prostate cancer cells. Combination effect of orlistat and RT was further investigated in both LNCaP and PC3 tumour-bearing mice. Combination treatment showed the best tumour inhibition compared to that of orlistat alone or RT alone. These results suggest that prostate cancer treated by conventional RT could be improved by orlistat via inhibition of FASN.

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Activation of the Androgen Receptor gene by BORIS/CTCFL in prostate cancer cells

10.1101/195875 ◽

2017 ◽

Author(s):

Yukti Hari-Gupta ◽

Georgia-Xanthi Kita ◽

Dawn Farrar ◽

Elena Klenova

Keyword(s):

Prostate Cancer ◽

Androgen Receptor ◽

Cancer Cells ◽

Transcriptional Activation ◽

Critical Role ◽

Prostate Gland ◽

Biologically Active ◽

Ctcf Binding ◽

Prostate Cancer Cells ◽

Prostate Cancers

AbstractBORIS/CTCFL, a paralogue of the chromatin architectural protein CTCF, is a member of the cancer-testis antigen family, normally present in the testes. BORIS is expressed in various tumours, including prostate cancers, however the function of BORIS in cancer cells is not well defined. The androgen receptor (AR) plays a critical role in the normal development of a human prostate gland and pathogenesis of prostate cancer. In our previous study we described a positive correlation between elevated levels of BORIS and AR in prostate cancers, and activation of the AR gene by BORIS in prostate cancer cells. Elucidation of the mechanisms involved in the modulation of AR activity is important to understand prostate tumourigenesis and investigation of transcriptional regulation of the AR gene by BORIS may provide new insights into this issue. Here we report the ability of BORIS to not only positively regulate AR in androgen-dependent prostate cancer (ADPC) cells, but re-activate epigenetically silenced AR in androgen-independent prostate cancer (AIPC) cells leading to the production of biologically active AR protein. CTCF, on the other hand, had repressive effects on the AR. In both, ADPC and AIPC cells, introduction of ectopic BORIS was associated with the reduction in the AR promoter methylation, increase in active and decrease in repressive chromatin marks, and decrease in CTCF occupancies at the two main upstream BORIS/CTCF binding sites. We propose a model of epigenetic regulation of AR by BORIS in prostate cells whereby BORIS remodels the chromatin at the AR promoter leading to transcriptional activation.

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